U.S. patent application number 12/089008 was filed with the patent office on 2009-04-23 for pyrimidine derivatives and their use in therapy as well as the use of pyrimidine derivatives in the manufacture of a medicament for prevention and/or treatment of alzheimer's disease.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Lars Andersson, Erwan Arzel, Stefan Berg, Jeremy Burrows, Sven Hellberg, Fernando Huerta, Torben Pedersen, Tobias Rein, Didier Rotticci, Karin Staaf, Dominika Turek.
Application Number | 20090105252 12/089008 |
Document ID | / |
Family ID | 37906403 |
Filed Date | 2009-04-23 |
United States Patent
Application |
20090105252 |
Kind Code |
A1 |
Andersson; Lars ; et
al. |
April 23, 2009 |
Pyrimidine Derivatives and Their Use in Therapy as well as the Use
of Pyrimidine Derivatives in the Manufacture of a Medicament for
Prevention and/or Treatment of Alzheimer's Disease
Abstract
Compounds of formula I ##STR00001## wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9
are as defined in the specification as a base or a pharmaceutically
acceptable salt, solvate or solvate of salt thereof, processes for
their preparation, new intermediates used therein, pharmaceutical
formulations containing said compounds and to the use of said
compounds in therapy.
Inventors: |
Andersson; Lars;
(Sodertalje, SE) ; Arzel; Erwan; (Sodertalje,
SE) ; Berg; Stefan; (Sodertalje, SE) ;
Burrows; Jeremy; (Sodertalje, SE) ; Hellberg;
Sven; (Sodertalje, SE) ; Huerta; Fernando;
(Sodertalje, SE) ; Pedersen; Torben; (Sodertalje,
SE) ; Rein; Tobias; (Sodertalje, SE) ;
Rotticci; Didier; (Sodertalje, SE) ; Staaf;
Karin; (Sodertalje, SE) ; Turek; Dominika;
(Sodertalje, SE) |
Correspondence
Address: |
ASTRA ZENECA PHARMACEUTICALS LP;GLOBAL INTELLECTUAL PROPERTY
1800 CONCORD PIKE
WILMINGTON
DE
19850-5437
US
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
37906403 |
Appl. No.: |
12/089008 |
Filed: |
October 2, 2006 |
PCT Filed: |
October 2, 2006 |
PCT NO: |
PCT/SE2006/001116 |
371 Date: |
April 21, 2008 |
Current U.S.
Class: |
514/235.8 ;
514/252.19; 514/275; 544/122; 544/331 |
Current CPC
Class: |
A61P 25/16 20180101;
A61K 31/506 20130101; C07D 409/14 20130101; A61P 25/00 20180101;
A61P 3/10 20180101; A61P 25/28 20180101; C07D 405/14 20130101; C07D
403/04 20130101; C07D 401/14 20130101 |
Class at
Publication: |
514/235.8 ;
544/331; 514/275; 514/252.19; 544/122 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 403/02 20060101 C07D403/02; A61K 31/506 20060101
A61K031/506; C07D 413/14 20060101 C07D413/14; A61P 25/28 20060101
A61P025/28; C07D 403/14 20060101 C07D403/14; A61K 31/496 20060101
A61K031/496 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 3, 2005 |
SE |
0502174-6 |
Claims
1-30. (canceled)
31. A compound of formula I: ##STR00211## wherein R.sup.1 is
selected from hydrogen, cyano, C.sub.1-3haloalkyl, OR.sup.a,
SO.sub.2NR.sup.bR.sup.c, C.sub.0-2alkylC(O)NR.sup.bR.sup.c,
C.sub.1-4alkylNR.sup.bR.sup.c, CH.sub.2OR.sup.h, SO.sub.2R.sup.i,
C(O)OR.sup.a, CH(OH)R.sup.j and C(O)R.sup.j; R.sup.2 and R.sup.4
are independently selected from hydrogen, halo, cyano, NO.sub.2,
C.sub.1-4alkyl, C.sub.1-3haloalkyl, OR.sup.a, C(O)NR.sup.bR.sup.c,
SO.sub.2R.sup.i and C(O)OR.sup.a; or R.sup.1 and R.sup.2, together
with the atoms to which they are attached form a 5- or 6-membered
heterocyclic ring containing at least one N, O or S, in which any
of the hydrogens of the CH.sub.2-groups within said heterocyclic
ring can be substituted with oxo, hydroxy or halo and in which any
sulphur atom within said heterocyclic ring is optionally oxidised
to --SO.sub.2--; R.sup.3 and R.sup.5 are hydrogen; R.sup.6 is
tetrahydropyran; R.sup.7 is selected from hydrogen, C.sub.1-3alkyl,
cyano and C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally substituted with one or more
OR.sup.a; R.sup.8 is hydrogen; R.sup.9 is hydrogen or fluoro;
R.sup.a is selected from hydrogen, C.sub.1-3alkyl and
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally substituted with one or more
C.sub.1-3alkoxy; R.sup.b and R.sup.c are independently selected
from hydrogen, C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl and
C.sub.1-6haloalkyl, wherein said C.sub.1-6alkyl, heterocyclyl,
aryl, heteroaryl or C.sub.1-6haloalkyl is optionally substituted
with one or more C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano,
methanesulphonyl-, OR.sup.a or NR.sup.dR.sup.e; or R.sup.b and
R.sup.c may, together with the atom to which they are attached,
form a heterocyclic ring wherein said heterocyclic ring is
optionally substituted with one or more halo, hydroxy, cyano,
di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or C.sub.1-3haloalkyl,
wherein said C.sub.1-6alkyl or C.sub.1-3haloalkyl is optionally
further substituted with one or more C.sub.1-3alkoxy or OR.sup.a;
R.sup.d and R.sup.e are independently selected from hydrogen,
C.sub.1-6alkyl and C.sub.1-6haloalkyl, wherein said C.sub.1-6alkyl
or C.sub.1-6haloalkyl is optionally substituted with one or more
OR.sup.a; or R.sup.d and R.sup.e may, together with the atom to
which they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
C.sub.1-3alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy; R.sup.h is hydrogen, C.sub.1-3alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally substituted with one or more
C.sub.1-3alkoxy; R.sup.i is selected from C.sub.1-6alkyl,
heterocyclyl, aryl, heteroaryl and C.sub.1-3haloalkyl, wherein said
C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl or
C.sub.1-3haloalkyl is optionally substituted with one or more halo,
cyano, di-(C.sub.1-4alkyl)amino-, C.sub.1-3haloalkyl,
C.sub.1-3alkyl, heterocyclyl or OR.sup.a; R.sup.j is an aryl or
heteroaryl ring, wherein said aryl or heteroaryl ring is optionally
substituted with one or more C.sub.1-3alkyl, OR.sup.a, halo or
cyano; as a base or a pharmaceutically acceptable salt, solvate or
solvate of a salt thereof.
32. (canceled)
33. A compound according to claim 31, wherein R.sup.1 is selected
from hydrogen, cyano, C.sub.1-3haloalkyl, SO.sub.2NR.sup.bR.sup.c,
C.sub.0-2alkylC(O)NR.sup.bR.sup.c, C.sub.1-4alkylNR.sup.bR.sup.c,
SO.sub.2R.sup.i, C(O)OR.sup.3, CH(OH)R.sup.j and C(O)R.sup.j;
R.sup.2 and R.sup.4 are independently selected from hydrogen, halo,
cyano, NO.sub.2, C.sub.1-4alkyl, C.sub.1-3haloalkyl, OR.sup.a,
SO.sub.2R.sup.i, C(O)NR.sup.bR.sup.c and C(O)OR.sup.a; or R.sup.1
and R.sup.2, together with the atoms to which they are attached
join to form a 5- or 6-membered heterocyclic ring containing at
least one N, O or S, in which any of the hydrogens of the
CH.sub.2-groups within the said heterocyclic ring can be
substituted with oxo, hydroxy or halo and in which any sulphur atom
within said heterocyclic ring is optionally oxidised to
--SO.sub.2--; R.sup.3 and R.sup.5 are hydrogen; R.sup.6 is
tetrahydropyran; R.sup.7 is selected from C.sub.1-3alkyl, cyano,
and C.sub.1-3haloalkyl; R.sup.8 is hydrogen; R.sup.9 is hydrogen or
fluoro; R.sup.a is selected from hydrogen, C.sub.1-3alkyl and
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl is optionally
substituted with one or more C.sub.1-3alkoxy; R.sup.b and R.sup.c
are independently selected from hydrogen, C.sub.1-6alkyl and
heterocyclyl, wherein said C.sub.1-6alkyl, heterocyclyl is
optionally substituted with one or more cyano, OR.sup.a or
NR.sup.dR.sup.e; or R.sup.b and R.sup.c may, together with the atom
to which they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
hydroxy, cyano, di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a; R.sup.d and R.sup.e are
independently selected from C.sub.1-6alkyl; or R.sup.d and R.sup.e
may, together with the atom to which they are attached, form a
heterocyclic ring wherein said heterocyclic ring is optionally
substituted with one or more halo; R.sup.i is selected from
C.sub.1-6alkyl and heterocyclyl, wherein said C.sub.1-6alkyl or
heterocyclyl is optionally substituted with one or more
di-(C.sub.1-4alkyl)amino-, heterocyclyl or OR.sup.a; R.sup.j is an
aryl or heteroaryl ring, wherein said aryl or heteroaryl ring is
optionally substituted with one or more C.sub.1-3alkyl; as a base
or a pharmaceutically acceptable salt, solvate or solvate of a salt
thereof.
34-37. (canceled)
38. A compound according to claim 31 or 33, wherein R.sup.7 is
methyl or trifluoromethyl.
39. A compound according to claim 31 or 33, wherein R.sup.4 is
selected from hydrogen, halo, NO.sub.2, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OR.sup.a, SO.sub.2R.sup.i, C(O)NR.sup.bR.sup.c
or C(O)OR.sup.3.
40. A compound according to claim 39, wherein R.sup.4 is
C(O)NR.sup.bR.sup.c and wherein R.sup.b and R.sup.c are
independently selected from hydrogen and C.sub.1-6alkyl, wherein
said C.sub.1-6alkyl is optionally substituted with one or more
OR.sup.a and wherein R.sup.a is C.sub.1-3alkyl.
41. A compound according to claim 39, wherein R.sup.4 is
trifluoromethyl.
42. A compound according to claim 39, wherein R.sup.4 is
chloro.
43. A compound according to claim 39, wherein R.sup.a is
trifluoromethyl.
44. A compound according to claim 38, wherein R.sup.2 is hydrogen,
halo, C.sub.1-3alkyl or OR.sup.a.
45. A compound according to claim 44, wherein R.sup.2 is
chloro.
46. A compound according to claim 44, wherein R.sup.1 is selected
from hydrogen, cyano, C.sub.1-3haloalkyl, SO.sub.2NR.sup.bR.sup.c,
C.sub.0-2alkylC(O)NR.sup.bR.sup.c, C.sub.1-4alkylNR.sup.bR.sup.c,
SO.sub.2R.sup.i, C(O)OR.sup.a, CH(OH)R.sup.j or C(O)R.sup.j.
47. A compound according to claim 46, wherein R.sup.1 is
C.sub.0-2alkylC(O)NR.sup.bR.sup.c and R.sup.b and R.sup.c are
independently selected from hydrogen, C.sub.1-6alkyl, heterocyclyl,
aryl, heteroaryl and C.sub.1-6haloalkyl, wherein said
C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl or
C.sub.1-6haloalkyl is optionally substituted with one or more
C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano, methanesulphonyl-,
OR.sup.a or NR.sup.dR.sup.e; or R.sup.b and R.sup.c may, together
with the atom to which they are attached, form a heterocyclic ring
wherein said heterocyclic ring is optionally substituted with one
or more halo, hydroxy, cyano, di-(C.sub.1-4alkyl)amino-,
C.sub.1-6alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a.
48. A compound according to claim 47, wherein R.sup.b and R.sup.c
together with the atom to which they are attached, form a
heterocyclic ring, wherein said heterocyclic ring is optionally
substituted with one or more halo, C.sub.1-6alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a.
49. A compound according to claim 48, wherein said a heterocyclic
ring is substituted with methyl.
50. A compound according to claim 46, wherein R.sup.1 is
C.sub.1-4alkylNR.sup.bR.sup.c and R.sup.b and R.sup.c together with
the atom to which they are attached, form a heterocyclic ring.
51. A compound according to claim 46, wherein R.sup.1 is
SO.sub.2R.sup.i and R.sup.i is C.sub.1-6alkyl, wherein said
C.sub.1-6alkyl is optionally substituted with one or more
OR.sup.a.
52. A compound according to claim 51, wherein R.sup.i is
methyl.
53. A compound according to claim 46, wherein R.sup.1 is
SO.sub.2NR.sup.bR.sup.c and R.sup.b and R.sup.c are independently
selected from hydrogen, C.sub.1-6alkyl, heterocyclyl, aryl,
heteroaryl and C.sub.1-6haloalkyl, wherein said C.sub.1-6alkyl,
heterocyclyl, aryl, heteroaryl or C.sub.1-6haloalkyl is optionally
substituted with one or more C.sub.1-4alkyl, C.sub.1-4haloalkyl,
halo, cyano, methanesulphonyl-, OR.sup.a or NR.sup.dR.sup.e; or
R.sup.b and R.sup.c may, together with the atom to which they are
attached, form a heterocyclic ring wherein said heterocyclic ring
is optionally substituted with one or more halo, hydroxy, cyano,
di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or C.sub.1-3haloalkyl,
wherein said C.sub.1-6alkyl or C.sub.1-3haloalkyl is optionally
further substituted with one or more C.sub.1-3alkoxy or
OR.sup.a.
54. A compound according to claim 53, wherein R.sup.b and R.sup.c
together with the atom to which they are attached form a
heterocyclic ring, wherein said heterocyclic ring is optionally
substituted with one or more halo, C.sub.1-6alkyl or
C.sub.1-3haloalkyl.
55. A compound according to claim 54, wherein said heterocyclic
ring is substituted with a C.sub.1-6alkyl.
56. A compound according to claim 55, wherein said C.sub.1-6alkyl
is methyl.
57. A compound according to claim 31, wherein said compound is
selected from:
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-
-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-{3-methoxy-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-me-
thyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)carbonyl]-3-(methylsulfonyl)phenyl-
]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-am-
ine hydrochloride;
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)sulfonyl]-3-(trifluoromethoxy)phen-
yl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2--
amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(pyrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(morpholin-4-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]p-
yrimidin-2-yl}amino)phenyl] (pyridin-2-yl)methanone hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(morpholin-4-ylmethyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperidin-1-ylcarbonyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(trifluoromethyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-N-[3-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride;
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride;
3-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzonitrile hydrochloride;
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzonitrile hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperazin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride; or
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[1-(tetrahydro--
2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride as a base or an alternative salt thereof.
58. A compound according to claim 31, said compound being selected
from:
N-{4-[(Dimethylamino)methyl]phenyl}-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-
-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(1-morpholin-4-ylethyl)phenyl]pyrimidin-2-amine;
N-[4-(1-Azetidin-1-ylethyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H--
pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(2-morpholin-4-ylethyl)phenyl]pyrimidin-2-amine;
N-[4-(Methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H--
imidazol-5-yl]pyrimidin-2-amine;
N-{4-[(4-Methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{4-[(4-Methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholi-
n-4-ylmethyl)phenyl]pyrimidin-2-amine;
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholi-
n-4-ylsulfonyl)phenyl]pyrimidin-2-amine;
N-(4-{[4-(2-Methoxyethyl)piperazin-1-yl]sulfonyl}phenyl)-4-[2-methyl-1-(t-
etrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{4-[(4-Isopropylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahyd-
ro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(pyrrolid-
in-1-ylsulfonyl)phenyl]pyrimidin-2-amine;
(N-(1-Methylpiperidin-4-yl)-4-({4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)--
1H-imidazol-5-yl]pyrimidin-2-yl}amino)benzenesulfonamide;
N-{4-[(4-Methyl-1,4-diazepan-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahy-
dro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N,N-Diethyl-4-({4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl-
]pyrimidin-2-yl}amino)benzenesulfonamide;
N-[4-(Azetidin-1-ylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4--
yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{3-[(4-Methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{3-Methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-(4-{[(3R)-3-methylmorpholin-4-yl]sulfonyl}phenyl)-4-[2-methyl--
1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-{3-methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-met-
hyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-(4-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfony-
l}phenyl)-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine;
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)-N,N-dimethylbenzenesulfonamide;
N-[4-(Azetidin-1-ylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-
-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; Ethyl
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate;
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(-
trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-[4-(Azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[1-(tetrahydro-2H-pyran-4--
yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-met-
hyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-[4-(isopropylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyr-
an-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-[4-(Ethylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-
-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-{4-[(2-methoxyethyl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-
-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-(4-{[2-(Diethylamino)ethyl]sulfonyl}phenyl)-5-fluoro-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
2-{[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-y-
l]pyrimidin-2-yl}amino)phenyl]sulfonyl}ethanol;
{5-Fluoro-4-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}--
[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine;
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimidin--
4-yl}-1-(tetrahydro-pyran-4-yl)-1H-imidazole-2-carbonitrile; or
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimid-
in-2-yl}-[4-(tetrahydro-pyran-2-ylmethanesulfonyl)-phenyl]-amine;
or a pharmaceutically acceptable salt thereof.
59. A compound according to claim 31, said compound being selected
from:
N-[4-(Azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-
-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride;
N-{4-[(3,3-Difluoroazetidin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-methyl-1--
(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methyl-1-(tetra-
hydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-{4-[(4-fluoropiperidin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
N,N-Diethyl-4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imid-
azol-5-yl]pyrimidin-2-yl}amino)benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(3-methoxypropyl)benzamide hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(1,4-oxazepan-4-yl)methanone hydrochloride;
(4-ethylpiperazin-1-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-i-
midazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone hydrochloride;
(2,6-dimethylmorpholin-4-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-
-yl-imidazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(3-fluoropyrrolidin-1-yl)-methanone
hydrochloride;
(3,3-difluoropyrrolidin-1-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran--
4-yl-imidazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-methyl-benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-tetrahydropyran-4-yl-benzamide hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(3-hydroxypyrrolidin-1-yl)-methanone
hydrochloride;
N-(2-cyanoethyl)-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol--
4-yl)-pyrimidin-2-yl]amino-N-methyl-benzamide hydrochloride;
N-ethyl-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyr-
imidin-2-yl]amino-N-(2-hydroxyethyl)benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(2-hydroxyethyl)-N-methyl-benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(2-hydroxyethyl)benzamide hydrochloride;
N-(2-dimethylaminoethyl)-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-i-
midazol-4-yl)-pyrimidin-2-yl]amino-benzamide hydrochloride;
(4-dimethylamino-1-piperidyl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran--
4-yl-imidazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-[4-(2-methoxyethyl)piperazin-1-yl]-methanone
hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-[2-(1-piperidyl)ethyl]benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(2-morpholinoethyl)benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-isopropyl-benzamide hydrochloride;
N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-[5-fluoro-4-(2-methyl-3-tetrah-
ydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-yl]amino-benzamide
hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(4-isopropylpiperazin-1-yl)-methanone
hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(4-methyl-1,4-diazepan-1-yl)-methanone
hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-tetrahydrofuran-3-yl-benzamide hydrochloride;
[4-[5-Fluoro-4-[3-tetrahydropyran-4-yl-2-(trifluoromethyl)imidazol-4-yl]--
pyrimidin-2-yl]aminophenyl]-(4-methylpiperazin-1-yl)-methanone
hydrochloride;
5-Fluoro-N-[3-(methylsulfonyl)-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methy-
l-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-[4-(methylsulfonyl)-3-(trifluoromethyl)phenyl]-4-[2-methyl-1-(-
tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
6-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide
hydrochloride; or
6-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)thiochroman-4-ol 1,1-dioxide hydrochloride; ad
as a base or alternative salt thereof.
60-61. (canceled)
62. A compound selected from:
2-Chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine;
2-Methyl-4-[(4-methylpiperazin-1-yl)carbonyl]aniline;
4-[(4-Methylpiperazin-1-yl)carbonyl]-3-nitroaniline;
4-[(4-Methylpiperazin-1-yl)carbonyl]-2-(trifluoromethoxy)aniline;
4-[N-Acetyl-N-(tetrahydro-2H-pyran-4-yl)]amino-5-methylisoxazole;
5-Acetyl-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole;
(2E)-3-Dimethylamino-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-
-5-yl]prop-2-en-1-one;
(2Z)-3-Dimethylamino-2-fluoro-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-
-imidazol-5-yl]prop-2-en-1-one;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine; 1-(4-Chloro-2-methoxybenzoyl)-4-methylpiperazine;
1-[4-Bromo-2-(methylsulfonyl)benzoyl]-4-methylpiperazine;
4-(N-Acetyl-N-cyclohexyl)amino-5-methylisoxazole;
5-Acetyl-1-cyclohexyl-2-methyl-1H-imidazole;
(2E)-3-Dimethylamino-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)prop-2-en--
1-one;
(2Z)-3-Dimethylamino-2-fluoro-1-(1-cyclohexyl-2-methyl-1H-imidazol--
5-yl)prop-2-en-1-one;
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine;
5-Acetyl-2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazole;
(2E)-3-Dimethylamino-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-
-yl]prop-2-en-1-one;
(2Z)-3-Dimethylamino-2-fluoro-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-i-
midazol-5-yl]prop-2-en-1-one;
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]pyrimidi-
n-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine;
1-(tert-Butoxycarbonyl)-4-(4-bromo-benzenesulfonyl)-piperazine;
5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-1H-imidazole;
(2E)-3-Dimethylamino-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-1H-
-imidazol-5-yl]prop-2-en-1-one;
(2Z)-3-Dimethylamino-2-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluoro-
methyl-1H-imidazol-5-yl]prop-2-en-1-one;
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-amine;
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; 1-[(4-Bromo-2-chlorophenyl)sulfonyl]-4-methylpiperazine;
(3R)-4-[(4-Bromophenyl)sulfonyl]-3-methylmorpholine;
(1S,4S)-2-[(4-Bromophenyl)sulfonyl]-5-methyl-2,5-diazabicyclo
[2.2.1]heptane; Methyl 4-bromo-2-(trifluoromethoxy)benzoate;
4-Bromo-2-(trifluoromethoxy)benzoic acid;
4-(4-Chloro-2-methylbenzyl)morpholine; Lithium
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate; 1-(4-Bromo-2-methylbenzoyl)azetidine;
4-Bromo-2-(trifluoromethoxy)benzoic acid;
1-[4-Bromo-2-(trifluoromethoxy)benzoyl]azetidine;
2,2,2-Trifluoro-N-methyl-N-(5-methylisoxazol-4-yl)acetamide;
1-[1-Methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]ethanone;
(2E)-3-(Dimethylamino)-1-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]p-
rop-2-en-1-one;
(2Z)-3-(Dimethylamino)-2-fluoro-1-[1-methyl-2-(trifluoromethyl)-1H-imidaz-
ol-5-yl]prop-2-en-1-one;
5-Fluoro-4-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; 4-[4-Bromo-2-(methylsulfonyl)benzyl]morpholine;
2-[(4-Bromophenyl)sulfonyl]ethyl methyl ether;
2-[(4-Bromophenyl)sulfonyl]ethyl diethyl-amine;
N-(5-Methyl-isoxazol-4-yl)-N-(tetrahydro-pyran-4-yl)-formamide;
5-Acetyl-1-(tetrahydro-pyran-4-yl)-1H-imidazole;
(E)-3-Dimethylamino-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-propen-
one;
(Z)-3-Dimethylamino-2-fluoro-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-
-4-yl]-propenone;
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; and
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyr-
imidin-4-yl}-1-(tetrahydro-pyran-4-yl)-1H-imidazole-2-carbaldehyde.
63. (canceled)
64. A pharmaceutical formulation comprising as active ingredient a
therapeutically effective amount of a compound according to claim
31, in association with pharmaceutically acceptable excipients,
carriers or diluents.
65. (canceled)
66. A method of prevention and/or treatment of dementia,
Alzheimer's Disease, Parkinson's Disease, Frontotemporal dementia
Parkinson's Type, Parkinson dementia complex of Guam, HIV dementia,
diseases with associated neurofibrillar tangle pathologies and
dementia pugilistica, comprising administering to a mammal,
including man in need of such prevention and/or treatment, a
therapeutically effective amount of a compound of formula I as
defined in claim 31.
67. The method according to claim 66, wherein the disease is
Alzheimer's Disease.
68. A method of prevention and/or treatment of predemented states,
Mild Cognitive Impairment, Age-Associated Memory Impairment,
Age-Related Cognitive Decline, Cognitive Impairment No Dementia,
mild cognitive decline, mild neurocognitive decline, Late-Life
Forgetfulness, memory impairment and cognitive impairment, vascular
dementia, dementia with Lewy bodies, Frontotemporal dementia and
androgenetic alopecia and Type I and Type II diabetes, diabetic
neuropathy and diabetes related disorders, comprising administering
to a mammal, including man in need of such prevention and/or
treatment, a therapeutically effective amount of a compound of
formula I as defined in claim 31.
69. (canceled)
70. A method pr preventing or treating a condition selected from
dementia, Alzheimer's Disease, Parkinson's Disease, Frontotemporal
dementia Parkinson's Type, Parkinson dementia complex of Guam, HIV
dementia, diseases with associated neurofibrillar tangle
pathologies and dementia pugilistica, amyotrophic lateral
sclerosis, corticobasal degeneration, Down syndrome, Huntington's
Disease, postencephelatic parkinsonism, progressive supranuclear
palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma
and other chronic neurodegenerative diseases, bipolar disorder,
affective disorders, depression, schizophrenia or cognitive
disorders, comprising administering to a subject in need of such
prevention or treatment, a therapeutically effective amount of a
compound of formula I: ##STR00212## wherein R.sup.1 is selected
from hydrogen, halo, cyano, NO.sub.2, C.sub.1-3alkyl,
C.sub.1-3haloalkyl, OR.sup.a, SO.sub.2NR.sup.bR.sup.c,
C.sub.0-2alkylC(O)NR.sup.bR.sup.c, C.sub.1-4alkylNR.sup.bR.sup.c,
CH.sub.2OR.sup.h, SO.sub.2R.sup.i, C(O)OR.sup.a, CH(OH)R.sup.j and
C(O)R.sup.j; R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OR.sup.a, SO.sub.2NR.sup.bR.sup.c,
C(O)NR.sup.bR.sup.c, CH.sub.2NR.sup.bR.sup.c, CH.sub.2OR.sup.h,
SO.sub.2R.sup.i, C(O)OR.sup.a and C(O)R.sup.j; or R.sup.1 and
R.sup.2, together with the atoms to which they are attached join to
form a 5- or 6-membered heterocyclic ring containing at least one
N, O or S, in which any --CH.sub.2-group of said heterocyclic ring
can be substituted with oxo, hydroxy or halo and in which any
sulphur atom within said heterocyclic ring is optionally oxidised
to --SO.sub.2--; R.sup.3 and R.sup.5 are independently selected
from hydrogen, halo, cyano, C.sub.1-3alkyl, C.sub.1-3haloalkyl and
OR.sup.a; R.sup.6 is selected from CH.sub.3 and C.sub.6alkyl,
C.sub.6alkenyl, C.sub.6alkynyl and C.sub.6haloalkyl; or R.sup.6 is
a 6-membered heterocyclic ring containing one or more heteroatoms
selected from N, O or S, wherein said heterocyclic ring is
optionally substituted with one or more C.sub.1-3alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy; R.sup.7 is selected from hydrogen,
C.sub.1-3alkyl, cyano, and C.sub.1-3haloalkyl, wherein said
C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally substituted with
one or more OR.sup.a; R.sup.3 and R.sup.9 are independently
selected from hydrogen, cyano and halo; R.sup.a is selected from
hydrogen, C.sub.1-3alkyl and C.sub.1-3haloalkyl, wherein said
C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally substituted with
one or more C.sub.1-3alkoxy; R.sup.b and R.sup.c are independently
selected from hydrogen, C.sub.1-6alkyl, heterocyclyl, aryl,
heteroaryl and C.sub.1-6haloalkyl, wherein said C.sub.1-6alkyl,
heterocyclyl, aryl, heteroaryl or C.sub.1-6haloalkyl is optionally
substituted with one or more C.sub.1-4alkyl, C.sub.1-4haloalkyl,
halo, cyano, methanesulphonyl-, OR.sup.a or NR.sup.dR.sup.e; or
R.sup.b and R.sup.c may, together with the atom to which they are
attached, form a heterocyclic ring wherein said heterocyclic ring
is optionally substituted with one or more halo, hydroxy, cyano,
di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or C.sub.1-3haloalkyl,
wherein said C.sub.1-6alkyl or C.sub.1-3haloalkyl is optionally
further substituted with one or more C.sub.1-3alkoxy or OR.sup.a;
R.sup.d and R.sup.e are independently selected from hydrogen,
C.sub.1-6alkyl and C.sub.1-6haloalkyl, wherein said C.sub.1-6alkyl
or C.sub.1-6haloalkyl is optionally substituted with one or more
OR.sup.a; or R.sup.d and R.sup.e may, together with the atom to
which they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
C.sub.1-3alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy; R.sup.h is hydrogen, C.sub.1-3alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally substituted with one or more
C.sub.1-3alkoxy; R.sup.i is C.sub.1-6alkyl, heterocyclyl, aryl,
heteroaryl or C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl,
heterocyclyl, aryl, heteroaryl or C.sub.1-3haloalkyl is optionally
substituted with one or more halo, cyano,
di-(C.sub.1-4alkyl)amino-, C.sub.1-3haloalkyl, C.sub.1-3alkyl,
heterocyclyl or OR.sup.a; R.sup.j is an aryl or heteroaryl ring,
wherein said aryl or heteroaryl ring is optionally substituted with
one or more C.sub.1-3alkyl, OR.sup.a, halo or cyano; as a base or a
pharmaceutically acceptable salt, solvate or solvate of a salt
thereof.
71. A method according to claim 70, wherein said compound is a
compound in accord with formula I or formula Ia, wherein; R.sup.6
is selected from CH.sub.3 and C.sub.6alkyl; or R.sup.6 is a
6-membered heterocyclic ring containing one or more heteroatoms
selected from N, O or S, wherein said heterocyclic ring is
optionally substituted with one or more C.sub.1-3alkyl or
C.sub.1-3haloalkyl; as a base or a pharmaceutically acceptable
salt, solvate or solvate of a salt thereof.
72. A method according to claim 70, wherein said compound is a
compound in accord with formula I and R.sup.3 and R.sup.5 are
hydrogen.
73. A method according to claim 72, wherein R.sup.8 is hydrogen and
R.sup.9 is hydrogen or fluoro.
74. A method according to claim 73, wherein R.sup.6 is
tetrahydropyran.
75. A method according to claim 72 or 73, wherein R.sup.7 is methyl
or trifluoromethyl.
76. A method according to claim 72, wherein R.sup.4 is selected
from hydrogen, halo, NO.sub.2, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OR.sup.a, SO.sub.2R.sup.i, C(O)NR.sup.bR.sup.c and
C(O)OR.sup.a.
77. A method according to claim 72, wherein R.sup.4 is
C(O)NR.sup.bR.sup.c and wherein R.sup.b and R.sup.c are
independently selected from hydrogen and C.sub.1-6alkyl, wherein
said C.sub.1-6alkyl is optionally substituted with one or more
OR.sup.a and wherein R.sup.a is C.sub.1-3alkyl.
78. A method according to claim 72, wherein R.sup.2 is hydrogen,
halo, C.sub.1-3alkyl or OR.sup.a.
79. A method according to claim 78, wherein R.sup.1 is selected
from hydrogen, cyano, C.sub.1-3haloalkyl, SO.sub.2NR.sup.bR.sup.c,
C.sub.0-2alkylC(O)NR.sup.bR.sup.c, C.sub.1-4alkylNR.sup.bR.sup.c,
SO.sub.2R.sup.i, C(O)OR.sup.a, CH(OH)R.sup.j and C(O)R.sup.j.
80. A method according to claim 79, wherein: R.sup.1 is
C.sub.0-2alkylC(O)NR.sup.bR.sup.1 and R.sup.b and R.sup.c are
independently selected from hydrogen, C.sub.1-6alkyl, heterocyclyl,
aryl, heteroaryl and C.sub.1-6haloalkyl, wherein said
C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl or
C.sub.1-6haloalkyl is optionally substituted with one or more
C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano, methanesulphonyl-,
OR.sup.a or NR.sup.dR.sup.e; or R.sup.b and R.sup.c may, together
with the atom to which they are attached, form a heterocyclic ring
wherein said heterocyclic ring is optionally substituted with one
or more halo, hydroxy, cyano, di-(C.sub.1-4alkyl)amino-,
C.sub.1-6alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a.
81. A method according to claim 80, wherein R.sup.b and R.sup.c
together with the atom to which they are attached, form a
heterocyclic ring, wherein said heterocyclic ring is optionally
substituted with one or more halo, C.sub.1-6alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a.
82. A method according to claim 81, wherein said heterocyclic ring
is substituted with methyl.
83. A method according to claim 79, wherein R.sup.1 is
C.sub.1-4alkylNR.sup.bR.sup.c and R.sup.b and R.sup.c together with
the atom to which they are attached, form a heterocyclic ring.
84. A method according to claim 70, wherein the condition is
bipolar disorder.
85. A method pr preventing or treating a subject afflicted with a
condition selected from dementia, Alzheimer's Disease, Parkinson's
Disease, Frontotemporal dementia Parkinson's Type, Parkinson
dementia complex of Guam, HIV dementia, diseases with associated
neurofibrillar tangle pathologies and dementia pugilistica,
amyotrophic lateral sclerosis, corticobasal degeneration, Down
syndrome, Huntington's Disease, postencephelatic parkinsonism,
progressive supranuclear palsy, Pick's Disease, Niemann-Pick's
Disease, stroke, head trauma and other chronic neurodegenerative
diseases, bipolar disorder, affective disorders, depression,
schizophrenia or cognitive disorders, comprising administering to a
subject in need of such prevention or treatment, a therapeutically
effective amount of a compound selected from:
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[3-methoxy-5-(trifluoromethy-
l)phenyl]pyrimidin-2-amine;
N-(3,5-Dichlorophenyl)-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidi-
n-2-amine;
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]a-
mino}phenyl)(phenyl)methanone;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{2-methyl-4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]-3-nitrophenyl}pyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-[(4-methylpiperazin-1-yl)-
carbonyl]-2-(trifluoromethoxy)phenyl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-{3-methoxy-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-me-
thyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)carbonyl]-3-(methylsulfonyl)phenyl-
]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-am-
ine hydrochloride;
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)sulfonyl]-3-(trifluoromethoxy)phen-
yl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2--
amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(pyrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(morpholin-4-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]p-
yrimidin-2-yl}amino)phenyl] (pyridin-2-yl)methanone hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(morpholin-4-ylmethyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperidin-1-ylcarbonyl)phenyl]pyrimidin-2-amine hydrochloride;
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine hydrochloride;
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)sulfonyl]phenyl}pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-{4-[(-
4-methylpiperazin-1-yl)carbonyl]phenyl}pyrimidin-2-amine
hydrochloride;
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-[4-(p-
yrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(trifluoromethyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-N-[3-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride;
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride;
3-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzonitrile hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(morpholin-4-ylmethyl)phe-
nyl]pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
sulfonyl]phenyl}pyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(piperidin-1-ylcarbonyl)p-
henyl]pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]phenyl}pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
methyl]phenyl}pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-[(4-methylpiperazin-1-yl)-
carbonyl]phenyl}pyrimidin-2-amine hydrochloride;
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pheny-
l)(pyridin-2-yl)methanone hydrochloride;
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzonitrile hydrochloride;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperazin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[1-(tetrahydro--
2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
N-{4-[(Dimethylamino)methyl]phenyl}-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-
-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(1-morpholin-4-ylethyl)phenyl]pyrimidin-2-amine;
N-[4-(1-Azetidin-1-ylethyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H--
pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(2-morpholin-4-ylethyl)phenyl]pyrimidin-2-amine;
N-[4-(Methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H--
imidazol-5-yl]pyrimidin-2-amine;
N-{4-[(4-Methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{4-[(4-Methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholi-
n-4-ylmethyl)phenyl]pyrimidin-2-amine;
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholi-
n-4-ylsulfonyl)phenyl]pyrimidin-2-amine;
N-(4-{[4-(2-Methoxyethyl)piperazin-1-yl]sulfonyl}phenyl)-4-[2-methyl-1-(t-
etrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{4-[(4-Isopropylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahyd-
ro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(pyrrolid-
in-1-ylsulfonyl)phenyl]pyrimidin-2-amine;
(N-(1-Methylpiperidin-4-yl)-4-({4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)--
1H-imidazol-5-yl]pyrimidin-2-yl}amino)benzenesulfonamide;
N-{4-[(4-Methyl-1,4-diazepan-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahy-
dro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N,N-Diethyl-4-({4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl-
]pyrimidin-2-yl}amino)benzenesulfonamide;
N-[4-(Azetidin-1-ylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4--
yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{3-[(4-Methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-{3-Methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-(4-{[(3R)-3-methylmorpholin-4-yl]sulfonyl}phenyl)-4-[2-methyl--
1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-{3-methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-met-
hyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-(4-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfony-
l}phenyl)-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine;
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)-N,N-dimethylbenzenesulfonamide;
N-[4-(Azetidin-1-ylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-
-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; Methyl
3-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}benzoa-
te;
3-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-N-(3--
methoxypropyl)benzamide hydrochloride;
[4-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2-(trif-
luoromethoxy)phenyl]-(4-methylpiperazin-1-yl)methanone
hydrochloride;
N-[4-(Azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-
-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride;
N-{4-[(3,3-Difluoroazetidin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-methyl-1--
(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methyl-1-(tetra-
hydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-[4-(morpholin-4-ylmethyl)phenyl]-4-[3-oxan-4-yl-2-(trifluorome-
thyl)imidazol-4-yl]-pyrimidin-2-amine hydrochloride;
5-Fluoro-N-{4-[(4-fluoropiperidin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; Ethyl
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-
-yl]pyrimidin-2-yl}amino)benzoate;
N,N-Diethyl-4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imid-
azol-5-yl]pyrimidin-2-yl}amino)benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(3-methoxypropyl)benzamide hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(1,4-oxazepan-4-yl)methanone hydrochloride;
(4-ethylpiperazin-1-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-i-
midazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone hydrochloride;
(2,6-dimethylmorpholin-4-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-
-yl-imidazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(3-fluoropyrrolidin-1-yl)-methanone
hydrochloride;
(3,3-difluoropyrrolidin-1-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran--
4-yl-imidazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-methyl-benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-tetrahydropyran-4-yl-benzamide hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(3-hydroxypyrrolidin-1-yl)-methanone
hydrochloride;
N-(2-cyanoethyl)-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol--
4-yl)-pyrimidin-2-yl]amino-N-methyl-benzamide hydrochloride;
N-ethyl-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyr-
imidin-2-yl]amino-N-(2-hydroxyethyl)benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(2-hydroxyethyl)-N-methyl-benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(2-hydroxyethyl)benzamide hydrochloride;
N-(2-dimethylaminoethyl)-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-i-
midazol-4-yl)-pyrimidin-2-yl]amino-benzamide hydrochloride;
(4-dimethylamino-1-piperidyl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran--
4-yl-imidazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-[4-(2-methoxyethyl)piperazin-1-yl]-methanone
hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-[2-(1-piperidyl)ethyl]benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(2-morpholinoethyl)benzamide hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-isopropyl-benzamide hydrochloride;
N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-[5-fluoro-4-(2-methyl-3-tetrah-
ydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-yl]amino-benzamide
hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(4-isopropylpiperazin-1-yl)-methanone
hydrochloride;
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(4-methyl-1,4-diazepan-1-yl)-methanone
hydrochloride;
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-tetrahydrofuran-3-yl-benzamide hydrochloride;
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(-
trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-[4-(Azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[1-(tetrahydro-2H-pyran-4--
yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-[4-(Azetidin-1-ylcarbonyl)-3-chlorophenyl]-4-(1,2-dimethyl-1H-imidazol--
5-yl)-5-fluoropyrimidin-2-amine;
N-[4-(Azetidin-1-ylcarbonyl)-3-methylphenyl]-4-(1,2-dimethyl-1H-imidazol--
5-yl)-5-fluoropyrimidin-2-amine;
N-[3-Chloro-4-(methylsulfonyl)phenyl]-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-
-fluoropyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(methylsulfonyl)phenyl]py-
rimidin-2-amine;
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-(1,2-dimethyl-1-
H-imidazol-5-yl)-5-fluoropyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-methyl-4-[(4-methylpipera-
zin-1-yl)sulfonyl]phenyl}pyrimidin-2-amine;
N-[4-(Azetidin-1-ylcarbonyl)-3-(trifluoromethoxy)phenyl]-4-(1,2-dimethyl--
1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine;
5-Fluoro-N-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]-4-[3-methyl-2-(trif-
luoromethyl)imidazol-4-yl]-pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-N-[4-(morpholin-4--
ylmethyl)phenyl]-pyrimidin-2-amine hydrochloride;
[4-[5-Fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-pyrimidin-2-yl-
]aminophenyl]-(4-methylpiperazin-1-yl)-methanone hydrochloride;
[4-[5-Fluoro-4-[3-tetrahydropyran-4-yl-2-(trifluoromethyl)imidazol-4-yl]--
pyrimidin-2-yl]aminophenyl]-(4-methylpiperazin-1-yl)-methanone
hydrochloride;
5-Fluoro-N-[3-(methylsulfonyl)-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methy-
l-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
5-Fluoro-N-[4-(methylsulfonyl)-3-(trifluoromethyl)phenyl]-4-[2-methyl-1-(-
tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride;
6-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide
hydrochloride;
6-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)thiochroman-4-ol 1,1-dioxide hydrochloride;
N-(3-Dimethylaminopropyl)-3-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyri-
midin-2-yl]amino]benzamide;
N-(3-Dimethylaminopropyl)-3-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyri-
midin-2-yl]amino]-N-methyl-benzamide hydrochloride;
[3-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]--
[3-(hydroxymethyl)-1-piperidyl]methanone;
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-met-
hyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pheny-
l)(pyridin-2-yl)methanol;
5-Fluoro-N-[4-(isopropylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyr-
an-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-[4-(Ethylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-
-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
5-Fluoro-N-{4-[(2-methoxyethyl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-
-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
N-(4-{[2-(Diethylamino)ethyl]sulfonyl}phenyl)-5-fluoro-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
2-{[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-y-
l]pyrimidin-2-yl}amino)phenyl]sulfonyl}ethanol;
{5-Fluoro-4-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}--
[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine;
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimidin--
4-yl}-1-(tetrahydro-pyran-4-yl)-1H-imidazole-2-carbonitrile; or
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimid-
in-2-yl}-[4-(tetrahydro-pyran-2-ylmethanesulfonyl)-phenyl]-amine,
as a base or a pharmaceutically acceptable salt, solvate or solvate
of a salt thereof.
86. A compound of formula J: ##STR00213## wherein R.sup.1 is
C.sub.0-2alkylC(O)NR.sup.bR.sup.c or C.sub.1-4alkylNR.sup.bR.sup.c;
R.sup.2 and R.sup.4 are independently selected from hydrogen or
C.sub.1-4alkyl; R.sup.3 and R.sup.5 are independently selected from
hydrogen or halo; R.sup.6 is a 6-membered heterocyclic ring
containing one or more heteroatoms selected from N, O or S; R.sup.7
is C.sub.1-3alkyl; R.sup.8 and R.sup.9 are independently selected
from hydrogen and halo, as a base or a pharmaceutically acceptable
salt, solvate or solvate of a salt thereof.
87. A compound selected from:
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[3-methoxy-5-(trifluoromethy-
l)phenyl]pyrimidin-2-amine;
N-(3,5-Dichlorophenyl)-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidi-
n-2-amine;
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]a-
mino}phenyl)(phenyl)methanone;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{2-methyl-4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]-3-nitrophenyl}pyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-[(4-methylpiperazin-1-yl)-
carbonyl]-2-(trifluoromethoxy)phenyl]pyrimidin-2-amine
hydrochloride;
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine hydrochloride;
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)sulfonyl]phenyl}pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-{4-[(-
4-methylpiperazin-1-yl)carbonyl]phenyl}pyrimidin-2-amine
hydrochloride;
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-[4-(p-
yrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(morpholin-4-ylmethyl)phe-
nyl]pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
sulfonyl]phenyl}pyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(piperidin-1-ylcarbonyl)p-
henyl]pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]phenyl}pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
methyl]phenyl}pyrimidin-2-amine hydrochloride;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-[(4-methylpiperazin-1-yl)-
carbonyl]phenyl}pyrimidin-2-amine hydrochloride, or
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pheny-
l)(pyridin-2-yl)methanone hydrochloride; or as a base or
alternative salt thereof.
88. A compound selected from: Methyl
3-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}benzoa-
te;
N-[4-(Azetidin-1-ylcarbonyl)-3-chlorophenyl]-4-(1,2-dimethyl-1H-imidaz-
ol-5-yl)-5-fluoropyrimidin-2-amine;
N-[4-(Azetidin-1-ylcarbonyl)-3-methylphenyl]-4-(1,2-dimethyl-1H-imidazol--
5-yl)-5-fluoropyrimidin-2-amine;
N-[3-Chloro-4-(methylsulfonyl)phenyl]-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-
-fluoropyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(methylsulfonyl)phenyl]py-
rimidin-2-amine;
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-(1,2-dimethyl-1-
H-imidazol-5-yl)-5-fluoropyrimidin-2-amine;
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-methyl-4-[(4-methylpipera-
zin-1-yl)sulfonyl]phenyl}pyrimidin-2-amine;
N-[4-(Azetidin-1-ylcarbonyl)-3-(trifluoromethoxy)phenyl]-4-(1,2-dimethyl--
1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine;
N-(3-Dimethylaminopropyl)-3-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyri-
midin-2-yl]amino]benzamide;
[3-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]--
[3-(hydroxymethyl)-1-piperidyl]methanone, or
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pheny-
l)(pyridin-2-yl)methanol; or a pharmaceutically acceptable salt
thereof.
89. A compound selected from:
3-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-N-(3-met-
hoxypropyl)benzamide hydrochloride;
[4-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2-(trif-
luoromethoxy)phenyl]-(4-methylpiperazin-1-yl)methanone
hydrochloride;
5-Fluoro-N-[4-(morpholin-4-ylmethyl)phenyl]-4-[3-oxan-4-yl-2-(trifluorome-
thyl)imidazol-4-yl]-pyrimidin-2-amine hydrochloride;
5-Fluoro-N-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]-4-[3-methyl-2-(trif-
luoromethyl)imidazol-4-yl]-pyrimidin-2-amine hydrochloride;
5-Fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-N-[4-(morpholin-4--
ylmethyl)phenyl]-pyrimidin-2-amine hydrochloride;
[4-[5-Fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-pyrimidin-2-yl-
]aminophenyl]-(4-methylpiperazin-1-yl)-methanone hydrochloride, or
N-(3-Dimethylaminopropyl)-3-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyri-
midin-2-yl]amino]-N-methyl-benzamide hydrochloride; or as a base or
alternative salt thereof.
Description
TECHNICAL FIELD OF INVENTION
[0001] The present invention relates to new compounds of formula I,
as a free base or a pharmaceutically acceptable salt, solvate or
solvate of salt thereof, to pharmaceutical formulations containing
said compounds and to the use of said compounds in therapy. The
present invention further relates to a process for the preparation
of compounds of formula I and to new intermediates used
therein.
BACKGROUND OF THE INVENTION
[0002] Glycogen synthase kinase 3 (GSK3) is a serine/threonine
protein kinase composed of two isoforms (.alpha. and .beta.), which
are encoded by distinct genes but are highly homologous within the
catalytic domain. GSK3 is highly expressed in the central and
peripheral nervous system. GSK3 phosphorylates several substrates
including tau, .beta.-catenin, glycogen is synthase, pyruvate
dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin
and growth factors activate protein kinase B, which phosphorylates
GSK3 on serine 9 residue and inactivates it.
Alzheimer's Disease (AD) Dementias, and Taupathies
[0003] AD is characterized by cognitive decline, cholinergic
dysfunction and neuronal death, neurofibrillary tangles and senile
plaques consisting of amyloid-.beta. deposits. The sequence of
these events in AD is unclear, but they are believed to be related.
Glycogen synthase kinase 3.beta. (GSK3.beta.) or Tau (.tau.)
phosphorylating kinase selectively phosphorylates the microtubule
associated protein r in neurons at sites that are
hyperphosphorylated in AD brains. Hyperphosphorylated protein r has
lower affinity for microtubules and accumulates as paired helical
filaments, which are the main components that constitute
neurofibrillary tangles and neuropil threads in AD brains. This
results in depolymerization of microtubules, which leads to dying
back of axons and neuritic dystrophy. Neurofibrillary tangles are
consistently found in diseases such as AD, amyotrophic lateral
sclerosis, parkinsonism-dementia of Gaum, corticobasal
degeneration, dementia pugilistica and head trauma, Down's
syndrome, postencephalatic parkinsonism, progressive supranuclear
palsy, Niemann-Pick's Disease and Pick's Disease. Addition of
amyloid-.beta. to primary hippocampal cultures results in
hyperphosphorylation of .tau. and a paired helical filaments-like
state via induction of GSK3.beta. activity, followed by disruption
of axonal transport and neuronal death (Imahori and Uchida., J.
Biochem 121:179-188, 1997). GSK3, preferentially labels
neurofibrillary tangles and has been shown to be active in
pre-tangle neurons in AD brains. GSK3 protein levels are also
increased by 50% in brain tissue from AD patients. Furthermore,
GSK3.beta. phosphorylates pyruvate dehydrogenase, a key enzyme in
the glycolytic pathway and prevents the conversion of pyruvate to
acetyl-Co-A (Hoshi et al., PNAS 93:2719-2723, 1996). Acetyl-Co-A is
critical for the synthesis of acetylcholine, a neurotransmitter
with cognitive functions. Thus, GSK3.beta. inhibition may have
beneficial effects in progression as well as the cognitive deficits
associated with Alzheimer's disease and other above-referred to
diseases.
Chronic and Acute Neurodegenerative Diseases
[0004] Growth factor mediated activation of the PI3K/Akt pathway
has been shown to play a key role in neuronal survival. The
activation of this pathway results in GSK3 D inhibition. Recent
studies (Bhat et. al., PNAS 97:11074-11079 (2000)) indicate that
GSK3.beta. activity is increased in cellular and animal models of
neurodegeneration such as cerebral ischemia or after growth factor
deprivation. For example, the active site phosphorylation was
increased in neurons vulnerable to apoptosis, a type of cell death
commonly thought to occur in chronic and acute degenerative
diseases such as Alzheimer's Disease, Parkinson's Disease,
amyotrophic lateral sclerosis, Huntington's Disease and HIV
dementia, ischemic stroke and head trauma. Lithium was
neuroprotective in inhibiting apoptosis in cells and in the brain
at doses that resulted in the inhibition of GSK3.beta.. Thus GSK3,
inhibitors could be useful in attenuating the course of
neurodegenerative diseases.
Bipolar Disorders (BD)
[0005] Bipolar Disorders are characterised by manic episodes and
depressive episodes. Lithium has been used to treat BD based on its
mood stabilising effects. The disadvantage of lithium is the narrow
therapeutic window and the danger of overdosing that can lead to
lithium intoxication. The recent discovery that lithium inhibits
GSK3 at therapeutic concentrations has raised the possibility that
this enzyme represents a key target of lithium's action in the
brain (Stambolic et al., Curr. Biol. 6:1664-1668, 1996; Klein and
Melton; PNAS 93:8455-8459, 1996). Inhibition of GSK30 may therefore
be of therapeutic relevance in the treatment of BD as well as in AD
patients that have affective disorders.
Schizophrenia
[0006] GSK3 is involved in signal transduction cascades of multiple
cellular processes, particularly during neural development.
Kozlovsky et al (Am J Psychiatry 2000 May; 157(5):831-3) found that
GSK30 levels were 41% lower in the schizophrenic patients than in
comparison subjects. This study indicates that schizophrenia
involves neurodevelopmental pathology and that abnormal GSK3
regulation could play a role in schizophrenia. Furthermore, reduced
.beta.-catenin levels have been reported in patients exhibiting
schizophrenia (Cotter et al., Neuroreport 9:1379-1383 (1998)).
Diabetes
[0007] Insulin stimulates glycogen synthesis in skeletal muscles
via the dephosphorylation and thus activation of glycogen synthase.
Under resting conditions, GSK3 phosphorylates and inactivates
glycogen synthase via dephosphorylation. GSK3 is also
over-expressed in muscles from Type II diabetic patients (Nikoulina
et al., Diabetes 2000 February; 49(2):263-71). Inhibition of GSK3
increases the activity of glycogen synthase thereby decreasing
glucose levels by its conversion to glycogen. GSK3 inhibition may
therefore be of therapeutic relevance in the treatment of Type I
and Type II diabetes and diabetic neuropathy.
Hair Loss
[0008] GSK3 phosphorylates and degrades .beta.-catenin.
.beta.-catenin is an effector of the pathway for keratonin
synthesis. .beta.-catenin stabilisation may be lead to increase
hair development. Mice expressing a stabilised .beta.-catenin by
mutation of sites phosphorylated by GSK3 undergo a process
resembling de novo hair morphogenesis (Gat et al., Cell 1998 Nov.
25; 95 (5):605-14)). The new follicles formed sebaceous glands and
dermal papilla, normally established only in embryogenesis. Thus
GSK3 inhibition may offer treatment for baldness.
Oral Contraceptives
[0009] Vijajaraghavan et al. (Biol Reprod 2000 June; 62
(6):1647-54) reported that GSK3 is high in motile versus immotile
sperm. Immunocytochemistry revealed that GSK3 is present in the
flagellum and the anterior portion of the sperm head. These data
suggest that GSK3 could be a key element underlying motility
initiation in the epididymis and regulation of mature sperm
function. Inhibitors of GSK3 could be useful as contraceptives for
males.
Bone-Related Disorders
[0010] It has been shown that GSK3 inhibitors could be used for
treatment of bone-related is disorders. This has been discussed in
e.g. Tobias et al., Expert Opinion on Therapeutic Targets, February
2002, pp 41-56.
DISCLOSURE OF THE INVENTION
[0011] The object of the present invention is to provide compounds
having a selective inhibiting effect at GSK3 as well as having a
good bioavailability.
[0012] The present invention therefore relates to the use of a
compound of the formula I:
##STR00002##
wherein
[0013] R.sup.1 is selected from hydrogen, halo, cyano, NO.sub.2,
C.sub.1-3alkyl, C.sub.1-3haloalkyl, OR.sup.a,
SO.sub.2NR.sup.bR.sup.c, C.sub.0-2alkylC(O)NR.sup.bR.sup.c,
C.sub.1-4alkylNR.sup.bR.sup.c, CH.sub.2OR.sup.h, SO.sub.2R.sup.i,
C(O)OR.sup.a, CH(OH)R.sup.j and C(O)R.sup.j;
[0014] R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OR.sup.a, SO.sub.2NR.sup.bR.sup.c,
C(O)NR.sup.bR.sup.c, CH.sub.2NR.sup.bR.sup.c, CH.sub.2OR.sup.h,
SO.sub.2R.sup.i, C(O)OR.sup.a and C(O)R.sup.j; or
[0015] R.sup.1 and R.sup.2, together with the atoms to which they
are attached join to form a 5- or 6-membered heterocyclic ring
containing at least one N, O or S, in which any of the hydrogens of
the CH.sub.2-groups within the said heterocyclic ring can be
substituted with oxo, hydroxy or halo and in which any sulphur atom
within said heterocyclic ring is optionally oxidised to
--SO.sub.2--;
[0016] R.sup.3 and R.sup.5 are independently selected from
hydrogen, halo, cyano, C.sub.1-3alkyl, C.sub.1-3haloalkyl and
OR.sup.a;
[0017] R.sup.6 is selected from CH.sub.3, C.sub.6alkyl,
C.sub.6alkenyl, C.sub.6alkynyl and C.sub.6haloalkyl; or
[0018] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N, O or S, wherein said heterocyclic
ring is optionally substituted with one or more C.sub.1-3alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy;
[0019] R.sup.7 is selected from hydrogen, C.sub.1-3alkyl, cyano,
and C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally substituted with one or more
OR.sup.a;
[0020] R.sup.8 and R.sup.9 are independently selected from
hydrogen, cyano and halo;
[0021] R.sup.a is selected from hydrogen, C.sub.1-3alkyl and
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally substituted with one or more
C.sub.1-3alkoxy;
[0022] R.sup.b and R.sup.c are independently selected from
hydrogen, C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl and
C.sub.1-6haloalkyl, wherein said C.sub.1-6alkyl, heterocyclyl,
aryl, heteroaryl or C.sub.1-6haloalkyl is optionally substituted
with one or more C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano,
methanesulphonyl-, OR.sup.a or NR.sup.dR.sup.e; or
[0023] R.sup.b and R.sup.c may, together with the atom to which
they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
hydroxy, cyano, di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a;
[0024] R.sup.d and R.sup.e are independently selected from
hydrogen, C.sub.1-6alkyl and C.sub.1-6haloalkyl, wherein said
C.sub.1-6alkyl or C.sub.1-6haloalkyl is optionally substituted with
one or more OR.sup.a; or
[0025] R.sup.d and R.sup.e may, together with the atom to which
they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
C.sub.1-3alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy;
[0026] R.sup.h is hydrogen, C.sub.1-3alkyl or C.sub.1-3haloalkyl,
wherein said C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally
substituted with one or more C.sub.1-3alkoxy;
[0027] R.sup.i is selected from C.sub.1-6alkyl, heterocyclyl, aryl,
heteroaryl and C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl,
heterocyclyl, aryl, heteroaryl or C.sub.1-3haloalkyl is optionally
substituted with one or more halo, cyano,
di-(C.sub.1-4alkyl)amino-, C.sub.1-3haloalkyl, C.sub.1-3alkyl,
heterocyclyl or OR.sup.a;
[0028] R.sup.j is an aryl or heteroaryl ring, wherein said aryl or
heteroaryl ring is optionally substituted is with one or more
C.sub.1-3alkyl, OR.sup.a, halo or cyano;
as a free base or a pharmaceutically acceptable salt, solvate or
solvate of a salt thereof; in the manufacture of a medicament for
prevention and/or treatment of dementia, Alzheimer's Disease,
Parkinson's Disease, Frontotemporal dementia Parkinson's Type,
Parkinson dementia complex of Guam, HIV dementia, diseases with
associated neurofibrillar tangle pathologies and dementia
pugilistica.
[0029] The present invention also relates to the use of a compound
of the formula Ia:
##STR00003##
wherein
[0030] R.sup.1 is selected from hydrogen, halo, cyano, NO.sub.2,
C.sub.1-3alkyl, C.sub.1-3haloalkyl, OR.sup.a,
SO.sub.2NR.sup.bR.sup.c, C(O)NR.sup.bR.sup.c,
CH.sub.2NR.sup.bR.sup.c, CH.sub.2OR.sup.h, SO.sub.2R.sup.i and
C(O)R.sup.j;
[0031] R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-3alkyl,
C.sub.1-3haloalkyl, OR.sup.a, SO.sub.2NR.sup.bR.sup.c,
C(O)NR.sup.bR.sup.c, CH.sub.2NR.sup.bR.sup.c, CH.sub.2OR.sup.h,
SO.sub.2R.sup.i and C(O)R.sup.j;
[0032] R.sup.3 and R.sup.5 independently are selected from
hydrogen, C.sub.1-3alkyl, C.sub.1-3haloalkyl and OR.sup.a;
[0033] R.sup.6 is selected from CH.sub.3, C.sub.6alkyl,
C.sub.6alkenyl, C.sub.6alkynyl, and C.sub.6haloalkyl; or
[0034] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N, O or S, wherein said heterocyclic
ring is optionally substituted with one or more C.sub.1-3alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy;
[0035] R.sup.7 is selected from C.sub.1-3alkyl, cyano, and
C.sub.1-3haloalkyl, said C.sub.1-3alkyl or C.sub.1-3haloalkyl is
optionally substituted with one or more OR.sup.a;
[0036] R.sup.8 and R.sup.9 are independently selected from
hydrogen, cyano and halo;
[0037] R.sup.10 is hydrogen;
[0038] R.sup.a is selected from hydrogen, C.sub.1-3alkyl and
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally substituted with one or more
C.sub.1-3alkoxy;
[0039] R.sup.b and R.sup.c are independently selected from
hydrogen, C.sub.1-6alkyl or C.sub.1-6haloalkyl, wherein aid
C.sub.1-6alkyl or C.sub.1-6haloalkyl is optionally substituted with
one or more OR.sup.a or NR.sup.dR.sup.e; or
[0040] R.sup.b and R.sup.c may, together with the atom to which
they are attached, form a 4-, 5- or 6-membered heterocyclic ring
containing one or more heteroatoms selected from N, O or S, wherein
said heterocyclic ring is optionally substituted with one or more
halo, C.sub.1-3alkyl or C.sub.1-3haloalkyl, said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy;
[0041] R.sup.d and R.sup.e are independently selected from
hydrogen, C.sub.1-6alkyl or C.sub.1-6haloalkyl, said C.sub.1-6alkyl
or C.sub.1-6haloalkyl is optionally substituted with one or more
OR.sup.a; or
[0042] R.sup.d and R.sup.e may, together with the atom to which
they are attached, form a 4-, 5- or 6-membered heterocyclic ring
containing one or more heteroatoms selected from N, O or S, wherein
said heterocyclic ring is optionally substituted with one or more
halo, C.sub.1-3alkyl or C.sub.1-3haloalkyl, said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy;
[0043] R.sup.h is hydrogen, C.sub.1-3alkyl or C.sub.1-3haloalkyl,
wherein said C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally
substituted with one or more C.sub.1-3alkoxy
[0044] R.sup.i is C.sub.1-3alkyl or C.sub.1-3haloalkyl, wherein
said C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally substituted
with one or more OR.sup.a;
[0045] R.sup.j is an aryl or heteroaryl ring, wherein said aryl or
heteroaryl ring is optionally substituted with one or more
C.sub.1-3alkyl, ORE, halo or cyano;
as a free base or a pharmaceutically acceptable salt, solvate or
solvate of a salt thereof; in the manufacture of a medicament for
prevention and/or treatment of dementia, Alzheimer's Disease,
Parkinson's Disease, Frontotemporal dementia Parkinson's Type,
Parkinson dementia complex of Guam, HIV dementia, diseases with
associated neurofibrillar tangle pathologies and dementia
pugilistica.
[0046] One embodiment of the present invention relates to the use
of a compound according to formula I or formula Ia, wherein
[0047] R.sup.1 is selected from hydrogen, cyano,
C.sub.1-3haloalkyl, SO.sub.2NR.sup.bR.sup.c, C(O)NR.sup.bR.sup.c,
CH.sub.2NR.sup.bR.sup.c, SO.sub.2R.sup.i and C(O)R.sup.j;
[0048] R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-3haloalkyl, ORE,
C(O)NR.sup.bR.sup.c, and SO.sub.2;
[0049] R.sup.3 and R.sup.5 independently are selected from
hydrogen, C.sub.1-3alkyl, and OR.sup.a;
[0050] R.sup.6 is selected from CH.sub.3, C.sub.6alkyl and
C.sub.6haloalkyl; or
[0051] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N, O or S, wherein said heterocyclic
ring is optionally substituted with one or more C.sub.1-3alkyl or
C.sub.1-3haloalkyl, said C.sub.1-3alkyl or C.sub.1-3haloalkyl is
optionally further substituted with one or more
C.sub.1-3alkoxy;
[0052] R.sup.7 is selected from C.sub.1-3alkyl, cyano, and
C.sub.1-3haloalkyl;
[0053] R.sup.10 is hydrogen;
[0054] R.sup.8 and R.sup.9 independently are selected from
hydrogen, cyano and halo;
[0055] R.sup.a is selected from hydrogen, C.sub.1-3alkyl and
C.sub.1-3haloalkyl, said C.sub.1-3alkyl or C.sub.1-3haloalkyl is
optionally substituted with one or more C.sub.1-3alkoxy;
[0056] R.sup.b and R.sup.c are independently selected from
hydrogen, C.sub.1-6alkyl or C.sub.1-6haloalkyl, said C.sub.1-6alkyl
or C.sub.1-6haloalkyl is optionally substituted with one or more
OR.sup.a; or
[0057] R.sup.b and R.sup.c may, together with the atom to which
they are attached, form a 4-, 5-, 6- or 7-membered heterocyclic
ring containing one or more heteroatoms selected from N, O or S,
wherein said heterocyclic ring is optionally substituted with one
or more halo, C.sub.1-3alkyl or C.sub.1-3haloalkyl, said
C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally further
substituted with one or more C.sub.1-3alkoxy;
[0058] R.sup.i is C.sub.1-3alkyl or C.sub.1-3haloalkyl, said
C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally substituted with
one or more OR.sup.a;
[0059] R.sup.j is an arylor heteroaryl ring, wherein said aryl or
heteroaryl ring is optionally substituted with one or more
C.sub.1-3alkyl, OR.sup.a, halo or cyano; as a free base or a
pharmaceutically acceptable salt, solvate or solvate of a salt
thereof.
[0060] One embodiment of the present invention provides the use of
the compound according to formula I or formula Ia wherein R.sup.6
is selected from CH.sub.3 and C.sub.6alkyl; or
[0061] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N, O or S, wherein said heterocyclic
ring is optionally substituted with one or more C.sub.1-3alkyl or
C.sub.1-3haloalkyl; as a free base or a pharmaceutically acceptable
salt, solvate or solvate of a salt thereof.
[0062] Another embodiment of the present invention provides the use
of the compound of formula I or formula Ia, wherein R.sup.1 is
selected from hydrogen, cyano, C.sub.1-3haloalkyl,
SO.sub.2NR.sup.bR.sup.c, C(O)NR.sup.bR.sup.c,
CH.sub.2NR.sup.bR.sup.c, SO.sub.2R.sup.i and C(O)R.sup.j;
[0063] R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-3haloalkyl, OR.sup.a,
C(O)NR.sup.bR.sup.c and SO.sub.2R.sup.i;
[0064] R.sup.3 and R.sup.5 independently are selected from
hydrogen, C.sub.1-3alkyl, and OR.sup.a;
[0065] R.sup.6 is selected from CH.sub.3 and C.sub.6alkyl; or
[0066] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N, O or S, wherein said heterocyclic
ring is optionally substituted with one or more C.sub.1-3alkyl or
C.sub.1-3haloalkyl;
[0067] R.sup.7 is selected from C.sub.1-3alkyl and
C.sub.1-3haloalkyl;
[0068] R.sup.10 is hydrogen;
[0069] R.sup.8 and R.sup.9 independently are selected from hydrogen
and halo;
[0070] R.sup.a is C.sub.1-3alkyl or C.sub.1-3haloalkyl;
[0071] R.sup.1 and R.sup.c are independently selected from
hydrogen, C.sub.1-6alkyl, said C.sub.1-6alkyl optionally
substituted with one or more OR.sup.a or
[0072] R.sup.b and R.sup.c may, together with the atom to which
they are attached, together form a 4-, 5- or 6-membered
heterocyclic ring containing one or more heteroatoms selected from
N, O or S, wherein said heterocyclic ring is optionally substituted
with one or more halo or C.sub.1-3alkyl;
[0073] R.sup.i is C.sub.1-3alkyl;
[0074] R.sup.j is an aryl or heteroaryl ring, wherein said aryl or
heteroaryl ring is optionally substituted with one or more
C.sub.1-3alkyl, OR.sup.a, halo or cyano
as a free base or a pharmaceutically acceptable salt, solvate or
solvate of a salt thereof.
[0075] Yet another additional embodiment of the present invention
provides the use of the compound according to formula I,
wherein
[0076] R.sup.1 is selected from hydrogen, cyano,
C.sub.1-3haloalkyl, SO.sub.2NR.sup.bR.sup.c,
C.sub.0-2alkylC(O)NR.sup.bR.sup.c, C.sub.1-4alkylNR.sup.bR.sup.c,
SO.sub.2R.sup.i, C(O)OR.sup.a, CH(OH)R.sup.j and C(O)R.sup.j;
[0077] R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OR.sup.a, SO.sub.2R.sup.i, C(O)NR.sup.bR.sup.c
and C(O)OR.sup.a; or
[0078] R.sup.1 and R.sup.2, together with the atoms to which they
are attached join to form a 5- or 6-membered heterocyclic ring
containing at least one N, O or S, in which any of the hydrogen sof
the CH.sub.2-groups within the said heterocyclic ring can be
substituted with oxo, hydroxy or halo and in which any sulphur atom
within said heterocyclic ring is optionally oxidised to
--SO.sub.2--;
[0079] R.sup.3 and R.sup.5 are independently selected from
hydrogen, C.sub.1-3alkyl, and OR.sup.a;
[0080] R.sup.6 is selected from CH.sub.3 and C.sub.6alkyl; or
[0081] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N or O, wherein said heterocyclic
ring is optionally substituted with one or more C.sub.1-3alkyl;
[0082] R.sup.7 is selected from C.sub.1-3alkyl, cyano, and
C.sub.1-3haloalkyl;
[0083] R.sup.8 and R.sup.9 are independently selected from hydrogen
and halo;
[0084] R.sup.a is selected from hydrogen, C.sub.1-3alkyl and
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl is optionally
substituted with one or more C.sub.1-3alkoxy;
[0085] R.sup.b and R.sup.c are independently selected from
hydrogen, C.sub.1-6alkyl and heterocyclyl, wherein said
C.sub.1-6alkyl, heterocyclyl is optionally substituted with one or
more cyano, OR.sup.a or NR.sup.dR.sup.e; or
[0086] R.sup.b and R.sup.c may, together with the atom to which
they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
hydroxy, cyano, di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a;
[0087] R.sup.d and R.sup.e are independently selected from hydrogen
and C.sub.1-6alkyl, wherein said C.sub.1-6alkyl is optionally
substituted with one or more OR.sup.a; or
[0088] R.sup.d and R.sup.e may, together with the atom to which
they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more
halo;
[0089] R.sup.i is selected from C.sub.1-6alkyl and heterocyclyl,
wherein said C.sub.1-6alkyl or heterocyclyl is optionally
substituted with one or more di-(C.sub.1-4alkyl)amino-,
heterocyclyl or OR.sup.a;
[0090] R.sup.j is an aryl or heteroaryl ring, wherein said aryl or
heteroaryl ring is optionally substituted with one or more
C.sub.1-3alkyl; as a free base or a pharmaceutically acceptable
salt, solvate or solvate of a salt thereof.
[0091] A further embodiment of the present invention relates to the
use of a compound according to formula I, wherein R.sup.3 and
R.sup.5 are hydrogen.
[0092] Yet a further embodiment of the present invention relates to
the use of a compound according to formula I, wherein R.sup.8 is
hydrogen and R.sup.9 is hydrogen or fluoro.
[0093] Another embodiment of the present invention relates to the
use of a compound according to formula I, wherein R.sup.6 is
C.sub.6alkyl. One additional embodiment of the present invention
provides the use of a compound according to formula I, wherein
R.sup.6 is tetrahydropyran.
[0094] Yet one additional embodiment of the present invention
provides the use of a compound according to formula I, wherein
R.sup.7 is methyl or trifluoromethyl.
[0095] One embodiment of the present invention provides the use of
a compound according to formula I, wherein R.sup.4 is selected from
hydrogen, halo, NO.sub.2, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OR.sup.a, SO.sub.2R.sup.i, C(O)NR.sup.bR.sup.c and C(O)OR.sup.a.
According to one additional embodiment of the present invention,
R.sup.4 is C(O)NR.sup.bR.sup.c and R.sup.b and R.sup.c are
independently selected from hydrogen and C.sub.1-6alkyl, and said
C.sub.1-6alkyl is optionally substituted with one or more OR.sup.a
and R.sup.a is C.sub.1-3alkyl. According to a further embodiment of
the present invention, R.sup.4 is trifluoromethyl. According to yet
another embodiment of the present invention R.sup.4 is chloro.
According to a further embodiment of the present invention, R.sup.a
is trifluoromethyl. Another embodiment of the present invention
relates to the use of a compound according to formula I, wherein
R.sup.2 is hydrogen, halo, C.sub.1-3alkyl or OR.sup.a. According to
one additional embodiment of the present invention, R.sup.2 is
chloro.
[0096] Yet another embodiment of the present invention provides the
use of a compound according to formula I, wherein R.sup.1 is
selected from hydrogen, cyano, C.sub.1-3haloalkyl,
SO.sub.2NR.sup.bR.sup.c, C.sub.0-2alkylC(O)NR.sup.bR.sup.c,
C.sub.1-4alkylNR.sup.bR.sup.c, SO.sub.2R.sup.i, C(O)OR.sup.a,
CH(OH)R.sup.j and C(O)R.sup.j. According to one additional
embodiment of the present invention, R.sup.1 is
C.sub.0-2alkylC(O)NR.sup.bR.sup.c and R.sup.b and R.sup.c are
independently selected from hydrogen, C.sub.1-6alkyl, heterocyclyl,
aryl, heteroaryl and C.sub.1-6haloalkyl, wherein said
C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl or
C.sub.1-6haloalkyl is optionally substituted with one or more
C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano, methanesulphonyl-,
OR.sup.a or NR.sup.dR.sup.e; or R.sup.b and R.sup.c may, together
with the atom to which they are attached, form a heterocyclic ring
wherein said heterocyclic ring is optionally substituted with one
or more halo, hydroxy, cyano, di-(C.sub.1-4alkyl)amino-,
C.sub.1-6alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a. According to one additional
embodiment of the present invention R.sup.b and R.sup.c, together
with the atom to which they are attached, form a heterocyclic ring,
wherein said heterocyclic ring is optionally substituted with one
or more halo, C.sub.1-6alkyl or C.sub.1-3haloalkyl, wherein said
C.sub.1-6alkyl or C.sub.1-3haloalkyl is optionally further
substituted with one or more C.sub.1-3alkoxy or OR.sup.a. According
to yet one additional embodiment of the present invention said
heterocyclic ring is substituted with methyl.
[0097] According to another embodiment of the present invention,
R.sup.1 is C.sub.1-4alkylNR.sup.bR.sup.c and R.sup.b and R.sup.c
together with the atom to which they are attached, form a
heterocyclic ring.
[0098] According to yet another embodiment of the present invention
R.sup.1 is SO.sub.2R.sup.i and k is C.sub.1-6alkyl, wherein said
C.sub.1-6alkyl is optionally substituted with one or more OR.sup.a.
According to one additional embodiment of the present invention
R.sup.i is methyl. According to one additional embodiment of the
present invention, R.sup.1 is SO.sub.2NR.sup.bR.sup.c and R.sup.b
and R.sup.c are independently selected from hydrogen,
C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl and
C.sub.1-6haloalkyl, wherein said C.sub.1-6alkyl, heterocyclyl,
aryl, heteroaryl or C.sub.1-6haloalkyl is optionally substituted
with one or more C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano,
methanesulphonyl-, OR.sup.a or NR.sup.dR.sup.d; or R.sup.b and
R.sup.c may, together with the atom to which they are attached,
form a heterocyclic ring wherein said heterocyclic ring is
optionally substituted with one or more halo, hydroxy, cyano,
di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or C.sub.1-3haloalkyl,
wherein said C.sub.1-6alkyl or C.sub.1-3haloalkyl is optionally
further substituted with one or more C.sub.1-3alkoxy or OR.sup.a.
According to a further additional embodiment of the present
invention, R.sup.b and R.sup.c, together with the atom to which
they are attached form a heterocyclic ring, wherein said
heterocyclic ring is optionally substituted with one or more halo,
C.sub.1-6alkyl or C.sub.1-3haloalkyl. According to a further
embodiment of the present invention said heterocyclic ring is
substituted with a C.sub.1-6alkyl. According to a further
embodiment of the present invention said C.sub.1-6alkyl is
methyl.
[0099] One embodiment of the present invention relates to the use
of a compound according to formula I, wherein said compound is
selected from: [0100]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[3-methoxy-5-(trifluo-
romethyl)phenyl]pyrimidin-2-amine; [0101]
N-(3,5-Dichlorophenyl)-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidi-
n-2-amine; [0102]
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pheny-
l)(phenyl)methanone; [0103]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{2-methyl-4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine; [0104]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]-3-nitrophenyl}pyrimidin-2-amine; [0105]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-[(4-methylpiperazin-1-yl)-
carbonyl]-2-(trifluoromethoxy)phenyl]pyrimidin-2-amine
hydrochloride; [0106]
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methy-
l-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0107]
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0108]
5-Fluoro-N-{3-methoxy-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}--
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amin-
e hydrochloride; [0109]
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)carbonyl]-3-(methylsulfonyl)phenyl-
]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-am-
ine hydrochloride; [0110]
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)sulfonyl]-3-(trifluoromethoxy)phen-
yl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2--
amine hydrochloride; [0111]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(pyrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
[0112]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(morpholin-4-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
[0113]
[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]p-
yrimidin-2-yl}amino)phenyl](pyridin-2-yl)methanone hydrochloride;
[0114]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(morpholin-4-ylmethyl)phenyl]pyrimidin-2-amine hydrochloride;
[0115]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperidin-1-ylcarbonyl)phenyl]pyrimidin-2-amine hydrochloride;
[0116]
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine hydrochloride; [0117]
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)sulfonyl]phenyl}pyrimidin-2-amine hydrochloride; [0118]
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-{4-[(-
4-methylpiperazin-1-yl)carbonyl]phenyl}pyrimidin-2-amine
hydrochloride; [0119]
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]--
N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine
hydrochloride; [0120]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl-
]-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine hydrochloride;
[0121]
5-Fluoro-N-[3-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride; [0122]
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride; [0123]
3-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzonitrile hydrochloride; [0124]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(morpholin-4-ylmethyl)phe-
nyl]pyrimidin-2-amine hydrochloride; [0125]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
sulfonyl]phenyl}pyrimidin-2-amine; [0126]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(piperidin-1-ylcarbonyl)p-
henyl]pyrimidin-2-amine hydrochloride; [0127]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]phenyl}pyrimidin-2-amine hydrochloride; [0128]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
methyl]phenyl}pyrimidin-2-amine hydrochloride; [0129]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-[(4-methylpiperazin-1-yl)-
carbonyl]phenyl}pyrimidin-2-amine hydrochloride; [0130]
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pheny-
l)(pyridin-2-yl)methanone hydrochloride; [0131]
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzonitrile hydrochloride; [0132]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperazin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
[0133]
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[1-(tetrahydro--
2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0134]
N-{4-[(Dimethylamino)methyl]phenyl}-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-
-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0135]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(1-morpholin-4-ylethyl)phenyl]pyrimidin-2-amine; [0136]
N-[4-(1-Azetidin-1-ylethyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H--
pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0137]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(2-morpholin-4-ylethyl)phenyl]pyrimidin-2-amine; [0138]
N-[4-(Methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H--
imidazol-5-yl]pyrimidin-2-amine; [0139]
N-{4-[(4-Methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0140]
N-{4-[(4-Methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0141]
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholi-
n-4-ylmethyl)phenyl]pyrimidin-2-amine; [0142]
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholi-
n-4-ylsulfonyl)phenyl]pyrimidin-2-amine; [0143]
N-(4-{[4-(2-Methoxyethyl)piperazin-1-yl]sulfonyl}phenyl)-4-[2-methyl-1-(t-
etrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0144]
N-{4-[(4-Isopropylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahyd-
ro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0145]
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(pyrrolid-
in-1-ylsulfonyl)phenyl]pyrimidin-2-amine; [0146]
(N-(1-Methylpiperidin-4-yl)-4-({4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)--
1H-imidazol-5-yl]pyrimidin-2-yl}amino)benzenesulfonamide; [0147]
N-{4-[(4-Methyl-1,4-diazepan-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahy-
dro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0148]
N,N-Diethyl-4-({4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl-
]pyrimidin-2-yl}amino)benzenesulfonamide; [0149]
N-[4-(Azetidin-1-ylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4--
yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0150]
N-{3-[(4-Methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0151]
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0152]
N-{3-Methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0153]
5-Fluoro-N-(4-{[(3R)-3-methylmorpholin-4-yl]sulfonyl}phenyl)-4-[2-methyl--
1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
[0154]
5-Fluoro-N-{3-methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-met-
hyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
[0155]
5-Fluoro-N-(4-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-
sulfonyl}phenyl)-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl-
]pyrimidin-2-amine; [0156]
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)-N,N-dimethylbenzenesulfonamide; [0157]
N-[4-(Azetidin-1-ylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-
-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0158] Methyl
3-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}benzoa-
te; [0159]
3-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino-
]-N-(3-methoxypropyl)benzamide hydrochloride; [0160]
[4-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2-(trif-
luoromethoxy)phenyl]-(4-methylpiperazin-1-yl)methanone
hydrochloride; [0161]
N-[4-(Azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrah-
ydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0162]
N-{4-[(3,3-Difluoroazetidin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-me-
thyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0163]
5-Fluoro-N-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methyl-1-(tetra-
hydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0164]
5-Fluoro-N-[4-(morpholin-4-ylmethyl)phenyl]-4-[3-oxan-4-yl-2-(trif-
luoromethyl)imidazol-4-yl]-pyrimidin-2-amine hydrochloride; [0165]
5-Fluoro-N-{4-[(4-fluoropiperidin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0166] Ethyl
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate; [0167]
N,N-Diethyl-4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imid-
azol-5-yl]pyrimidin-2-yl}amino)benzamide hydrochloride; [0168]
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(3-methoxypropyl)benzamide hydrochloride; [0169]
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(1,4-oxazepan-4-yl)methanone hydrochloride;
[0170]
(4-ethylpiperazin-1-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-i-
midazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone hydrochloride;
[0171]
(2,6-dimethylmorpholin-4-yl)-[4-[5-fluoro-4-(2-methyl-3-tetahydropyran-4--
yl-imdazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride; [0172]
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyr-
imidin-2-yl]aminophenyl]-(3-fluoropyrrolidin-1-yl)-methanone
hydrochloride; [0173]
(3,3-difluoropyrrolidin-1-yl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran--
4-yl-imidazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride; [0174]
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyri-
midin-2-yl]amino-N-methyl-benzamide hydrochloride; [0175]
4-[5-fluoro-4-(2-methyl-3-tetahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2--
yl]amino-N-tetrahydropyran-4-yl-benzamide hydrochloride; [0176]
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(3-hydroxypyrrolidin-1-yl)-methanone
hydrochloride; [0177]
N-(2-cyanoethyl)-4-[5-fluoro-4-(2-methyl-3-tetahydropyran-4-yl-imi-
dazol-4-yl)-pyrimidin-2-yl]amino-N-methyl-benzamide hydrochloride;
[0178]
N-ethyl-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyr-
imidin-2-yl]amino-N-(2-hydroxyethyl)benzamide hydrochloride; [0179]
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(2-hydroxyethyl)-N-methyl-benzamide hydrochloride;
[0180]
4-[5-fluoro-4-(2-methyl-3-tetahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2--
yl]amino-N-(2-hydroxyethyl)benzamide hydrochloride; [0181]
N-(2-dimethylaminoethyl)-4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-i-
midazol-4-yl)-pyrimidin-2-yl]amino-benzamide hydrochloride; [0182]
(4-dimethylamino-1-piperidyl)-[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran--
4-yl-imidazol-4-yl)-pyrimidin-2-yl]aminophenyl]-methanone
hydrochloride; [0183]
[4-[5-fluoro-4-(2-methyl-3-tetahydropyran-4-yl-imidazol-4-yl)-pyri-
midin-2-yl]aminophenyl]-[4-(2-methoxyethyl)piperazin-1-yl]-methanone
hydrochloride; [0184]
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-[2-(1-piperidyl)ethyl]benzamide hydrochloride; [0185]
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-(2-morpholinoethyl)benzamide hydrochloride; [0186]
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-isopropyl-benzamide hydrochloride; [0187]
N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-[5-fluoro-4-(2-methyl-3-tetrah-
ydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-yl]amino-benzamide
hydrochloride; [0188]
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin--
2-yl]aminophenyl]-(4-isopropylpiperazin-1-yl)-methanone
hydrochloride; [0189]
[4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyr-
imidin-2-yl]aminophenyl]-(4-methyl-1,4-diazepan-1-yl)-methanone
hydrochloride; [0190]
4-[5-fluoro-4-(2-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)-pyrimidin-2-
-yl]amino-N-tetrahydrofuran-3-yl-benzamide hydrochloride; [0191]
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(-
trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0192]
N-[4-(Azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[1-(tetrahydro-2H-pyran-4--
yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0193]
N-[4-(Azetidin-1-ylcarbonyl)-3-chlorophenyl]-4-(1,2-dimethyl-1H-imidazol--
5-yl)-5-fluoropyrimidin-2-amine; [0194]
N-[4-(Azetidin-1-ylcarbonyl)-3-methylphenyl]-4-(1,2-dimethyl-1H-imidazol--
5-yl)-5-fluoropyrimidin-2-amine; [0195]
N-[3-Chloro-4-(methylsulfonyl)phenyl]-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-
-fluoropyrimidin-2-amine; [0196]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(methylsulfonyl)phenyl]py-
rimidin-2-amine; [0197]
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-(1,2-dimethyl-1-
H-imidazol-5-yl)-5-fluoropyrimidin-2-amine; [0198]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-methyl-4-[(4-methylpipera-
zin-1-yl)sulfonyl]phenyl}pyrimidin-2-amine; [0199]
N-[4-(Azetidin-1-ylcarbonyl)-3-(trifluoromethoxy)phenyl]-4-(1,2-dimethyl--
1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine; [0200]
5-Fluoro-N-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]-4-[3-methyl-2-(trif-
luoromethyl)imidazol-4-yl]-pyrimidin-2-amine hydrochloride; [0201]
5-Fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-N-[4-(morpholin-4--
ylmethyl)phenyl]-pyrimidin-2-amine hydrochloride; [0202]
[4-[5-Fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-pyrimidin-2-yl-
]aminophenyl]-(4-methylpiperazin-1-yl)-methanone hydrochloride;
[0203]
[4-[5-Fluoro-4-[3-tetrahydropyran-4-yl-2-(trifluoromethyl)imidazol-4-yl]--
pyrimidin-2-yl]aminophenyl]-(4-methylpiperazin-1-yl)-methanone
hydrochloride; [0204]
5-Fluoro-N-[3-(methylsulfonyl)-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methy-
l-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0205]
5-Fluoro-N-[4-(methylsulfonyl)-3-(trifluoromethyl)phenyl]-4-[2-methyl-1-(-
tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0206]
6-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide
hydrochloride; [0207]
6-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)thiochroman-4-ol 1,1-dioxide hydrochloride;
[0208]
N-(3-Dimethylaminopropyl)-3-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyri-
midin-2-yl]amino]benzamide; [0209]
N-(3-Dimethylaminopropyl)-3-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyri-
midin-2-yl]amino]-N-methyl-benzamide hydrochloride;
[0210]
[3-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]p-
henyl]-[3-(hydroxymethyl)-1-piperidyl]methanone; [0211]
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-met-
hyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
[0212]
5-Fluoro-N-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methy-
l-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine;
[0213]
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pheny-
l)(pyridin-2-yl)methanol; [0214]
5-Fluoro-N-[4-(isopropylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyr-
an-4-yl)-1H-imidazol-5-yl]pyrimidin-2-anine; [0215]
N-[4-(Ethylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-
-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0216]
5-Fluoro-N-{4-[(2-methoxyethyl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-
-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0217]
N-(4-{[2-(Diethylamino)ethyl]sulfonyl}phenyl)-5-fluoro-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; [0218]
2-{[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-y-
l]pyrimidin-2-yl}amino)phenyl]sulfonyl}ethanol; [0219]
{5-Fluoro-4-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}--
[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine; [0220]
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimidin--
4-yl}-1-(tetrahydro-pyran-4-yl)-1H-imidazole-2-carbonitrile; and
[0221]
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimid-
in-2-yl}-[4-(tetrahydro-pyran-2-ylmethanesulfonyl)-phenyl]-amine.
in the manufacture of a medicament for prevention and/or treatment
of dementia, Alzheimer's Disease, Parkinson's Disease,
Frontotemporal dementia Parkinson's Type, Parkinson dementia
complex of Guam, HIV dementia, diseases with associated
neurofibrillar tangle pathologies and dementia pugilistica.
[0222] According to one embodiment of the present invention, the
disease is Alzheimer's Disease.
[0223] The present invention also relates to a compound of the
formula I:
##STR00004##
wherein
[0224] R.sup.1 is selected from hydrogen, cyano,
C.sub.1-3haloalkyl, OR.sup.a, SO.sub.2NR.sup.bR.sup.c,
C.sub.0-2alkylC(O)NR.sup.bR.sup.c, C.sub.1-4alkylNR.sup.bR.sup.c,
CH.sub.2OR.sup.h, SO.sub.2R.sup.i, C(O)OR.sup.a, CH(OH)R.sup.j and
C(O)R.sup.j;
[0225] R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OR.sup.a, C(O)NR.sup.bR.sup.c, SO.sub.2R.sup.i
and C(O)OR.sup.a; or
[0226] R.sup.1 and R.sup.2, together with the atoms to which they
are attached form a 5- or 6-membered heterocyclic ring containing
at least one N, O or S, in which any of the hydrogens of the
CH.sub.2-groups within said heterocyclic ring can be substituted
with oxo, hydroxy or halo and in which any sulphur atom within said
heterocyclic ring is optionally oxidised to --SO.sub.2--;
[0227] R.sup.3 and R.sup.5 are independently selected from
hydrogen, C.sub.1-3alkyl and OR.sup.a;
[0228] R.sup.6 is selected from CH.sub.3 and C.sub.6alkyl; or
[0229] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N, is O or S, wherein said
heterocyclic ring is optionally substituted with one or more
C.sub.1-3alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy;
[0230] R.sup.7 is selected from hydrogen, C.sub.1-3alkyl, cyano and
C.sub.1-3haloalkyl, wherein said C.sub.1-3aryl or
C.sub.1-3haloalkyl is optionally substituted with one or more
OR.sup.a;
[0231] R.sup.8 and R.sup.9 are independently are selected from
hydrogen and halo;
[0232] R.sup.a is selected from hydrogen, C.sub.1-3alkyl and
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl or
C.sub.1-3haloalkyl is optionally substituted with one or more
C.sub.1-3alkoxy;
[0233] R.sup.b and R.sup.c are independently selected from
hydrogen, C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl and
C.sub.1-6haloalkyl, wherein said C.sub.1-6alkyl, heterocyclyl,
aryl, heteroaryl or C.sub.1-6haloalkyl is optionally substituted
with one or more C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano,
methanesulphonyl-, OR.sup.a or NR.sup.dR.sup.e; or
[0234] R.sup.b and R.sup.c may, together with the atom to which
they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
hydroxy, cyano, di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a;
[0235] R.sup.d and R.sup.e are independently selected from
hydrogen, C.sub.1-6alkyl and C.sub.1-6haloalkyl, wherein said
C.sub.1-6alkyl or C.sub.1-6haloalkyl is optionally substituted with
one or more OR.sup.a; or
[0236] R.sup.d and R.sup.e may, together with the atom to which
they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
C.sub.1-3alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy;
[0237] R.sup.h is hydrogen, C.sub.1-3alkyl or C.sub.1-3haloalkyl,
wherein said C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally
substituted with one or more C.sub.1-3alkoxy;
[0238] R.sup.i is selected from C.sub.1-6alkyl, heterocyclyl, aryl,
heteroaryl and C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl,
heterocyclyl, aryl, heteroaryl or C.sub.1-3haloalkyl is optionally
substituted with one or more halo, cyano,
di-(C.sub.1-4alkyl)amino-, C.sub.1-3haloalkyl, C.sub.1-3alkyl,
heterocyclyl or OR.sup.a;
[0239] R.sup.j is an aryl or heteroaryl ring, wherein said aryl or
heteroaryl ring is optionally substituted with one or more
C.sub.1-3alkyl, OR.sup.a, halo or cyano;
as a free base or a pharmaceutically acceptable salt, solvate or
solvate of a salt thereof.
[0240] The present invention also relates to a compound of the
formula Ib:
##STR00005##
wherein
[0241] R.sup.1 is selected from hydrogen, cyano,
C.sub.1-3haloalkyl, SO.sub.2NR.sup.bR.sup.c, C(O)NR.sup.bR.sup.c,
CH.sub.2NR.sup.bR.sup.c, CH.sub.2OR.sup.h, SO.sub.2R.sup.i and
C(O)R.sup.j;
[0242] R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-3haloalkyl, OR.sup.a,
C(O)NR.sup.bR.sup.c, and SO.sub.2R.sup.i;
[0243] R.sup.3 and R.sup.5 independently are selected from
hydrogen, C.sub.1-3alkyl, and OR.sup.a;
[0244] R.sup.6 is selected from CH.sub.3 and C.sub.6alkyl; or
[0245] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N, or S, wherein said heterocyclic
ring is optionally substituted with one or more C.sub.1-3alkyl or
C.sub.1-3haloalkyl;
[0246] R.sup.7 is selected from C.sub.1-3alkyl and
C.sub.1-3haloalkyl;
[0247] R.sup.8 and R.sup.9 independently are selected from hydrogen
and halo;
[0248] R.sup.a is C.sub.1-3alkyl or C.sub.1-3haloalkyl;
[0249] R.sup.b and R.sup.c are independently selected from hydrogen
and C.sub.1-6alkyl, optionally substituted with one or more
OR.sup.a; or
[0250] R.sup.b and R.sup.c may, together with the atom to which
they are attached, form a 4-, 5- or 6-membered heterocyclic ring
containing one or more heteroatoms selected from N or O, wherein
said heterocyclic ring is optionally substituted with one or more
halo or C.sub.1-3alkyl;
[0251] R.sup.h is hydrogen, C.sub.1-3alkyl or C.sub.1-3haloalkyl,
wherein said C.sub.1-3alkyl or C.sub.1-3haloalkyl is optionally
substituted with one or more C.sub.1-3alkoxy;
[0252] R.sup.i is C.sub.1-3alkyl;
[0253] R.sup.j is an aryl or heteroaryl ring;
as a free base or a pharmaceutically acceptable salt, solvate or
solvate of a salt thereof.
[0254] One embodiment of the present invention relates to a
compound of formula I, wherein R.sup.1 is selected from hydrogen,
cyano, C.sub.1-3haloalkyl, SO.sub.2NR.sup.bR.sup.c,
C.sub.0-2alkylC(O)NR.sup.bR.sup.c, C.sub.1-4alkylNR.sup.bR.sup.c,
SO.sub.2R.sup.i, C(O)OR.sup.a, CH(OH)R.sup.j and C(O)R.sup.j;
[0255] R.sup.2 and R.sup.4 are independently selected from
hydrogen, halo, cyano, NO.sub.2, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OR.sup.a, SO.sub.2R.sup.i, C(O)NR.sup.bR.sup.c
and C(O)OR.sup.a; or
[0256] R.sup.1 and R.sup.2, together with the atoms to which they
are attached join to form a 5- or 6-membered heterocyclic ring
containing at least one N, O or S, in which any of the hydrogens of
the CH.sub.2-groups within the said heterocyclic ring can be
substituted with oxo, hydroxy or halo and in which any sulphur atom
within said heterocyclic ring is optionally oxidised to
--SO.sub.2--;
[0257] R.sup.3 and R.sup.5 are independently selected from
hydrogen, C.sub.1-3alkyl, and OR.sup.a;
[0258] R.sup.6 is selected from CH.sub.3 and C.sub.6alkyl; or
[0259] R.sup.6 is a 6-membered heterocyclic ring containing one or
more heteroatoms selected from N or O, wherein said heterocyclic
ring is optionally substituted with one or more C.sub.1-3alkyl;
[0260] R.sup.7 is selected from C.sub.1-3alkyl, cyano, and
C.sub.1-3haloalkyl;
[0261] R.sup.8 and R.sup.9 are independently selected from hydrogen
and halo;
[0262] R.sup.a is selected from hydrogen, C.sub.1-3alkyl and
C.sub.1-3haloalkyl, wherein said C.sub.1-3alkyl is optionally
substituted with one or more C.sub.1-3alkoxy;
[0263] R.sup.b and R.sup.c are independently selected from
hydrogen, C.sub.1-6alkyl and heterocyclyl, wherein said
C.sub.1-6alkyl, heterocyclyl is optionally substituted with one or
more cyano, OR.sup.a or NR.sup.dR.sup.e; or
[0264] R.sup.b and R.sup.c may, together with the atom to which
they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more halo,
hydroxy, cyano, di-(C.sub.1-4alkyl)amino-, C.sub.1-6alkyl or
C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl or
C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a;
[0265] R.sup.d and R.sup.e are independently selected from
C.sub.1-6alkyl; or
[0266] R.sup.d and R.sup.e may, together with the atom to which
they are attached, form a heterocyclic ring wherein said
heterocyclic ring is optionally substituted with one or more
halo;
[0267] R.sup.i is selected from C.sub.1-6alkyl and heterocyclyl,
wherein said C.sub.1-6alkyl or heterocyclyl is optionally
substituted with one or more di-(C.sub.1-4alkyl)amino-,
heterocyclyl or OR.sup.a;
[0268] R.sup.j is an aryl or heteroaryl ring, wherein said aryl or
heteroaryl ring is optionally substituted with one or more
C.sub.1-3alkyl; as a free base or a pharmaceutically acceptable
salt, solvate or solvate of a salt thereof.
[0269] Another embodiment of the present invention relates to a
compound of formula I, wherein R.sup.3 and R.sup.5 are
hydrogen.
[0270] Yet another embodiment of the present invention provides a
compound of formula I, wherein R.sup.8 is hydrogen and R.sup.9 is
hydrogen or fluoro.
[0271] A further embodiment of the present invention provides a
compound of formula I, wherein R.sup.6 is C.sub.6alkyl. According
to one additional embodiment of the present invention, R.sup.6 is
tetrahydropyran.
[0272] Yet another embodiment of the present invention provides a
compound of formula I, wherein R.sup.7 is methyl or
trifluoromethyl.
[0273] One embodiment of the present invention provides a compound
of formula I, wherein R.sup.4 is selected from hydrogen, halo,
NO.sub.2, C.sub.1-4alkyl, C.sub.1-3haloalkyl, OR.sup.a,
SO.sub.2R.sup.i, C(O)NR.sup.bR.sup.c and C(O)OR.sup.a. According to
another embodiment of the present invention, R.sup.b and R.sup.c
are independently selected from hydrogen and C.sub.1-6alkyl,
wherein said C.sub.1-6alkyl is optionally substituted with one or
more OR.sup.a and wherein R.sup.a is C.sub.1-3alkyl. According to
yet another embodiment of the present invention, R.sup.4 is
trifluoromethyl. According to one additional embodiment of the
present invention, R.sup.4 is chloro. According to yet one
additional embodiment of the present invention, R.sup.a is
trifluoromethyl.
[0274] One embodiment of the present invention provides a compound
of formula I, wherein R.sup.2 is hydrogen, halo, C.sub.1-3alkyl or
OR.sup.a. According to one additional embodiment of the present
invention, R.sup.2 is chloro.
[0275] Yet one embodiment of the present invention provides a
compound of formula I, wherein R.sup.1 is selected from hydrogen,
cyano, C.sub.1-3haloalkyl, SO.sub.2NR.sup.bR.sup.c,
C.sub.0-2alkylC(O)NR.sup.bR.sup.c, C.sub.1-4alkylNR.sup.bR.sup.c,
SO.sub.2R.sup.i, C(O)OR.sup.a, CH(OH)R.sup.j and C(O)R.sup.j.
According to one additional embodiment of the present invention,
R.sup.1 is C.sub.0-2alkylC(O)NR.sup.bR.sup.c and R.sup.b and
R.sup.c are independently selected from hydrogen, C.sub.1-6alkyl,
heterocyclyl, aryl, heteroaryl and C.sub.1-6haloalkyl, wherein said
C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl or
C.sub.1-6haloalkyl is optionally substituted with one or more
C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano, methanesulphonyl-,
OR.sup.a or NR.sup.dR.sup.e; or R.sup.b and R.sup.c may, together
with the atom to which they are attached, form a heterocyclic ring
wherein said heterocyclic ring is optionally substituted with one
or more halo, hydroxy, cyano, di-(C.sub.1-4alkyl)amino-,
C.sub.1-6alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a. According to yet one additional
embodiment of the present invention R.sup.b and R.sup.c, together
with the atom to which they are attached, form a heterocyclic ring,
wherein said heterocyclic ring is optionally substituted with one
or more halo, C.sub.1-6alkyl or C.sub.1-3haloalkyl, wherein said
C.sub.1-6alkyl or C.sub.1-3haloalkyl is optionally further
substituted with one or more C.sub.1-3alkoxy or OR.sup.a. According
to another embodiment of the present invention, said heterocyclic
ring is substituted with methyl.
[0276] According to a further embodiment of the present invention,
R.sup.1 is C.sub.1-4alkylNR.sup.bR.sup.c and R.sup.b and R.sup.c
together with the atom to which they are attached, form a
heterocyclic ring.
[0277] According to yet a further embodiment of the present
invention, SO.sub.2R.sup.1 and R.sup.1 is C.sub.1-6alkyl, wherein
said C.sub.1-6alkyl is optionally substituted with one or more
OR.sup.a. According to yet one additional embodiment of the present
invention R.sup.i is methyl.
[0278] According to another embodiment of the present invention,
R.sup.1 is SO.sub.2NR.sup.bR.sup.c and R.sup.b and R.sup.c are
independently selected from hydrogen, C.sub.1-6alkyl, heterocyclyl,
aryl, heteroaryl and C.sub.1-6haloalkyl, wherein said
C.sub.1-6alkyl, heterocyclyl, aryl, heteroaryl or
C.sub.1-6haloalkyl is optionally substituted with one or more
C.sub.1-4alkyl, C.sub.1-4haloalkyl, halo, cyano, methanesulphonyl-,
OR.sup.1 or NR.sup.dR.sup.e; or R.sup.b and R.sup.c may, together
with the atom to which they are attached, form a heterocyclic ring
wherein said heterocyclic ring is optionally substituted with one
or more halo, hydroxy, cyano, di-(C.sub.1-4alkyl)amino-,
C.sub.1-6alkyl or C.sub.1-3haloalkyl, wherein said C.sub.1-6alkyl
or C.sub.1-3haloalkyl is optionally further substituted with one or
more C.sub.1-3alkoxy or OR.sup.a. According to one additional
embodiment of the present invention, R.sup.b and R.sup.c together
with the atom to which they are attached form a heterocyclic ring,
wherein said heterocyclic ring is optionally substituted with one
or more halo, C.sub.1-6alkyl or C.sub.1-3haloalkyl. According to
yet one additional embodiment of the present invention said
heterocyclic ring is substituted with a C.sub.1-6alkyl. According
to yet a further additional embodiment of the present invention,
said C.sub.1-6alkyl is methyl.
[0279] One embodiment of the present invention provides a compound
of formula I selected from: [0280]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[3-methoxy-5-(trifluoromethy-
l)phenyl]pyrimidin-2-amine; [0281]
N-(3,5-Dichlorophenyl)-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidi-
n-2-amine; [0282]
(4-{[4-(1,2-Dimethyl-1H-imdazol-5-yl)-5-fluoropyrimidin-2-yl]amino}phenyl-
)(phenyl)methanone; [0283]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{2-methyl-4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine; [0284]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]-3-nitrophenyl}pyrimidin-2-amine; [0285]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-[(4-methylpiperazin-1-yl)-
carbonyl]-2-(trifluoromethoxy)phenyl]pyrimidin-2-amine
hydrochloride; [0286]
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methy-
l-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0287]
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride; [0288]
5-Fluoro-N-{3-methoxy-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}--
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amin-
e hydrochloride; [0289]
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)carbonyl]-3-(methylsulfonyl)phenyl-
]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-am-
ine hydrochloride; [0290]
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)sulfonyl]-3-(trifluoromethoxy)phen-
yl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2--
amine hydrochloride; [0291]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(pyrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
[0292]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(morpholin-4-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride;
[0293]
[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]p-
yrimidin-2-yl}amino)phenyl](pyridin-2-yl)methanone hydrochloride;
[0294]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(morpholin-4-ylmethyl)phenyl]pyrimidin-2-amine hydrochloride;
[0295]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperidin-1-ylcarbonyl)phenyl]pyrimidin-2-amine hydrochloride;
[0296]
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine hydrochloride; [0297]
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)sulfonyl]phenyl}pyrimidin-2-amine hydrochloride; [0298]
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-{4-[(-
4-methylpiperazin-1-yl)carbonyl]phenyl}pyrimidin-2-amine
hydrochloride; [0299]
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]--
N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine
hydrochloride; [0300]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl-
]-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine hydrochloride;
[0301]
5-Fluoro-N-[3-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride; [0302]
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran--
4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride; [0303]
3-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzonitrile hydrochloride; [0304]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(morpholin-4-ylmethyl)phe-
nyl]pyrimidin-2-amine hydrochloride; [0305]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
sulfonyl]phenyl}pyrimidin-2-amine; [0306]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(piperidin-1-ylcarbonyl)p-
henyl]pyrimidin-2-amine hydrochloride; [0307]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]phenyl}pyrimidin-2-amine hydrochloride; [0308]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
methyl]phenyl}pyrimidin-2-amine hydrochloride; [0309]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-[(4-methylpiperazin-1-yl)-
carbonyl]phenyl}pyrimidin-2-amine hydrochloride; [0310]
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pheny-
l)(pyridin-2-yl)methanone hydrochloride; [0311]
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzonitrile hydrochloride; [0312]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperazin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride; and
[0313]
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[1-(tetrahydro--
2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride.
[0314] One embodiment of the present invention relates to the
compounds disclosed above for use is in therapy.
[0315] The present invention also relates to a compound selected
from: [0316]
2-Chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine;
[0317] 2-Methyl-4-[(4-methylpiperazin-1-yl)carbonyl]aniline; [0318]
4-[(4-Methylpiperazin-1-yl)carbonyl]-3-nitroaniline; [0319]
4-[(4-Methylpiperazin-1-yl)carbonyl]-2-(trifluoromethoxy)aniline;
[0320]
4-[N-Acetyl-N-(tetrahydro-2H-pyran-4-yl)]amino-5-methylisoxazole;
[0321] 5-Acetyl-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole;
[0322]
(2E)-3-Dimethylamino-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-
-5-yl]prop-2-en-1-one; [0323]
(2Z)-3-Dimethylamino-2-fluoro-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-
-imidazol-5-yl]prop-2-en-1-one; [0324]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine; [0325]
1-(4-Chloro-2-methoxybenzoyl)-4-methylpiperazine; [0326]
1-[4-Bromo-2-(methylsulfonyl)benzoyl]-4-methylpiperazine; [0327]
4-(N-Acetyl-N-cyclohexyl)amino-5-methylisoxazole; [0328]
5-Acetyl-1-cyclohexyl-2-methyl-1H-imidazole; [0329]
(2E)-3-Dimethylamino-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)prop-2-en--
1-one; [0330]
(2Z)-3-Dimethylamino-2-fluoro-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)p-
rop-2-en-1-one; [0331]
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine;
[0332] 5-Acetyl-2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazole;
[0333]
(2E)-3-Dimethylamino-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-
-yl]prop-2-en-1-one; [0334]
(2Z)-3-Dimethylamino-2-fluoro-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-i-
midazol-5-yl]prop-2-en-1-one; [0335]
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]pyrimidi-
n-2-amine; [0336]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine; [0337]
1-(tert-Butoxycarbonyl)-4-(4-bromo-benzenesulfonyl)-piperazine;
[0338]
5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-1H-imidazole;
[0339]
(2E)-3-Dimethylamino-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluorome-
thyl-1H-imidazol-5-yl]prop-2-en-1-one; [0340]
(2Z)-3-Dimethylamino-2-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluoro-
methyl-1H-imidazol-5-yl]prop-2-en-1-one; [0341]
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-amine; [0342]
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; [0343] 1-[(4-Bromo-2-chlorophenyl)sulfonyl]-4-methylpiperazine;
[0344] (3R)-4-[(4-Bromophenyl)sulfonyl]-3-methylmorpholine; [0345]
(1S,4S)-2-[(4-Bromophenyl)sulfonyl]-5-methyl-2,5-diazabicyclo[2.2.1]hepta-
ne; [0346] Methyl 4-bromo-2-(trifluoromethoxy)benzoate; [0347]
4-Bromo-2-(trifluoromethoxy)benzoic acid; [0348]
4-(4-Chloro-2-methylbenzyl)morpholine; Lithium
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate; [0349]
1-(4-Bromo-2-methylbenzoyl)azetidine; [0350]
4-Bromo-2-(trifluoromethoxy)benzoic acid; [0351]
1-[4-Bromo-2-(trifluoromethoxy)benzoyl]azetidine; [0352]
2,2,2-Trifluoro-N-methyl-N-(5-methylisoxazol-4-yl)acetamide; [0353]
1-[1-Methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]ethanone; [0354]
(2E)-3-(Dimethylamino)-1-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]p-
rop-2-en-1-one; [0355]
(2Z)-3-(Dimethylamino)-2-fluoro-1-[1-methyl-2-(trifluoromethyl)-1H-imidaz-
ol-5-yl]prop-2-en-1-one; [0356]
5-Fluoro-4-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; [0357] 4-[4-Bromo-2-(methylsulfonyl)benzyl]morpholine; [0358]
2-[(4-Bromophenyl)sulfonyl]ethyl methyl ether; [0359]
2-[(4-Bromophenyl)sulfonyl]ethyl diethyl-amine; [0360]
N-(5-Methyl-isoxazol-4-yl)-N-(tetrahydro-pyran-4-yl)-formamide;
[0361] 5-Acetyl-1-(tetrahydro-pyran-4-yl)-1H-imidazole; [0362]
(E)-3-Dimethylamino-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-propen-
one; [0363]
(Z)-3-Dimethylamino-2-fluoro-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-y-
l]-propenone; [0364]
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; and [0365]
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimid
in-4-yl}-1-(tetrahydro-pyran-4-yl)-1H-imidazole-2-carbaldehyde.
[0366] The present invention also provides the use of the compounds
disclosed above for the preparation of a compound of formula I.
[0367] Listed below are definitions of various terms used in the
specification and claims to describe the present invention.
[0368] In this specification the term "alkyl" includes both
straight and branched chain as well as cyclic alkyl groups. The
term C.sub.1-3alkyl having 1 to 3 carbon atoms and may be, but is
not limited to, methyl, ethyl, n-propyl, i-propyl, or cyclopropyl.
The term C.sub.1-6alkyl having 1 to 6 carbon atoms and may be, but
is not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl,
neo-pentyl, n-hexyl, i-hexyl or cyclohexyl. The term C.sub.6alkyl
having 6 carbon atoms and may be, but is not limited to, n-hexyl,
i-hexyl or cyclohexyl. The term C.sub.1-4alkylNR.sup.bR.sup.c
includes, but is not limited to, --CH.sub.2NR.sup.bR.sup.c,
--CH.sub.2CH.sub.2NR.sup.bR.sup.c and
--CH(CH.sub.3)NR.sup.bR.sup.c. The term
C.sub.0-2alkylC(O)NR.sup.bR.sup.c is intended to include, but is
not limiting, C(O)NR.sup.bR.sup.c --CH.sub.2C(O)NR.sup.bR.sup.c,
--CH.sub.2CH.sub.2C(O)NR.sup.bR.sup.c and
--CH(CH.sub.3)C(O)NR.sup.bR.sup.c.
[0369] The term "alkenyl" refers to a straight or branched chain
alkenyl group. The term C.sub.6alkenyl having 6 carbon atoms and
one double bond, and may be, but is not limited to, hexenyl or
i-hexenyl.
[0370] The term "alkynyl" refers to a straight or branched chain
alkynyl group. The term C.sub.6alkynyl having 6 carbon atoms and
one triple bond, and may be, but is not limited to, hexynyl or
i-hexynyl.
[0371] The term "C.sub.1-3alkoxy" includes both straight and
branched chains. The term "C.sub.1-3alkoxy" having 1 to 3 carbon
atoms and may be, but is not limited to, methoxy, ethoxy,
n-propoxy, or i-propoxy.
[0372] The term "halogen" refers to fluorine, chlorine, bromine and
iodine.
[0373] The term "haloalkyl" refers to an alkyl group, defined as
above, in which one or more of the hydrogen substituents have been
replaced by halogen substituents, in which the term halogen is
defined as above. Examples include trifluoromethyl- and
difluoromethyl-.
[0374] The term "aryl" refers to an optionally substituted
monocyclic or bicyclic hydrocarbon ring system containing at least
one unsaturated aromatic ring. The "aryl" may be fused with a
C.sub.5-7cycloalkyl ring to form a bicyclic hydrocarbon ring
system. Examples and suitable values of the term "aryl", but not
limiting, are phenyl, naphthyl, indanyl or tetralinyl.
[0375] As used herein, "heteroaryl" refers to an aromatic
heterocycle having at least one heteroatom ring member such as
sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic
and polycyclic (e.g., having 2, 3 or 4 fused rings) systems.
Examples of heteroaryl groups include without limitation, pyridyl
(i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,
furyl (i.e. furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl,
thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl,
benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,
indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl,
carbazolyl, fluorenonyl, benzimidazolyl, indolinyl, and the like.
In some embodiments, the heteroaryl group has from 1 to about 20
carbon atoms, and in further embodiments from about 3 to about 20
carbon atoms. In some embodiments, the heteroaryl group contains 3
to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming
atoms. In some embodiments, the heteroaryl or heteroaromatic group
has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some
embodiments, the heteroaryl or heteroaromatic group has 1
heteroatom.
[0376] The term "heterocyclic ring" refers to a 4-, 5-, 6- or
7-membered ring containing one or more heteroatoms independently
selected from N, O, or S, said ring can be a mono- or bicyclic,
which may be saturated or partly saturated and which may optionally
contain a carbonyl function and which may be, but is not limited
to, azetidinyl, imidazolidinyl, imidazolinyl, morpholinyl,
piperazinyl, piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl,
pyrrolidinyl, pyrrolinyl, 1-methyl-1,4-diazepane, tetrahydropyranyl
or thiomorpholinyl. In the case where the heterocyclic ring
contains a heteroatom selected from S or N, these atoms may
optionally be in an oxidised form, such as S this includes
optionally SO and SO.sub.2.
[0377] The term "hydrochloride" includes monohydrochloride,
dihydrochloride, trihydrochloride and tetrahydrochloride salts.
[0378] A suitable pharmaceutically acceptable salt of the compound
of the invention is, for example, an acid-addition salt, for
example an inorganic or organic acid. In addition a suitable
pharmaceutically acceptable salt of the compounds of the invention
is an alkali metal salt, an alkaline earth metal salt or a salt
with an organic base that affords a physiologically-acceptable
cation.
[0379] Some compounds of formula I may have stereogenic centres
and/or geometric isomeric centres (E- and Z-isomers), and it is to
be understood that the invention encompasses all such optical,
diastereoisomers and geometric isomers.
[0380] The present invention relates to the use of compounds of
formula I as hereinbefore defined as well as to the salts thereof.
Salts for use in pharmaceutical compositions will be
pharmaceutically acceptable salts, but other salts may be useful in
the production of the compounds of formula I.
[0381] It is to be understood that the present invention relates to
any and all tautomeric forms of the compounds of formula I.
[0382] An object of the invention is to provide compounds of
formula I for therapeutic use, especially compounds that are useful
for the prevention and/or treatment of conditions associated with
glycogen synthase kinase-3 (GSK3) in mammals including man.
Particularly, compounds of formula I exhibiting a selective
affinity for GSK-3.
Methods of Preparation
[0383] Another aspect of the present invention provides a process
for preparing a compound of formula I, or a pharmaceutically
acceptable salt or an in vivo hydrolysable ester thereof, which
process (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8 and R.sup.9 and are, unless otherwise
specified, as defined in formula I) comprises of:
Process a) Reaction of a Pyrimidine of Formula (II):
##STR00006##
[0384] wherein L is a displaceable group; with an aniline of
formula (III):
##STR00007##
or
Process B) Reacting a Pyrimidine of Formula (IV):
##STR00008##
[0385] with a compound of formula (V):
##STR00009##
wherein Y is a displaceable group; and thereafter if necessary:
[0386] i) converting a compound of the formula I into another
compound of the formula I;
[0387] ii) removing any protecting groups; and
[0388] iii) forming a pharmaceutically acceptable salt or in vivo
hydrolysable ester.
[0389] L is a displaceable group, suitable values for L are for
example, a halogeno or sulphonyloxy group, for example a chloro,
bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.
[0390] Y is a displaceable group, suitable values for Y are for
example, a halogeno or sulphonyloxy group, for example a chloro,
bromo, iodo or trifluoromethanesulphonyloxy group. Preferably Y is
bromo or iodo.
[0391] Specific reaction conditions for the above reactions are as
follows.
[0392] Process a). Pyrimidines of formula (II) and anilines of
formula (III) may be reacted together under standard
Buchwald-Hartwig conditions (for example see J. Am. Chem. Soc.,
118, 7215; J. Am. Chem. Soc., 119, 8451; J. Am. Chem. Soc., 125,
6653; J. Org. Chem., 62, 1568 and 6066) for example in the presence
of palladium acetate, in a suitable solvent for example an aromatic
solvent such as toluene, benzene or xylene, with a suitable base
for example an inorganic base such as caesium carbonate or an
organic base such as potassium-t-butoxide, in the presence of a
suitable ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
or 2-dicyclohexylphosphino-2',4',6'-triiso-propyl-1,1'-biphenyl and
at a temperature in the range of +25 to +80.degree. C.
[0393] Pyrimidines of the formula (II), in which R.sup.6 is
CH.sub.3 and L is chloro, may be prepared according to Scheme
1:
##STR00010##
[0394] Anilines of formula (III) are commercially available
compounds, or they are known in the literature, or they are
prepared by standard processes known in the art.
[0395] Process b). Compounds of formula (IV) and amines of formula
(V) may be reacted together under standard Buchwald conditions as
described in Process a.
[0396] A synthesis of pyrimidines of formula (IV) is described in
Scheme 2(R.sup.x may be the same or different and is
C.sub.1-6alkyl):T should not be there
##STR00011##
[0397] Compounds of formula (V) are commercially available
compounds, or they are known in the literature, or they are
prepared by standard processes known in the art.
[0398] Compounds of formula (VI) in which R.sup.6 has the general
structure R.sup.a--CH--R.sup.b (wherein R.sup.a and R.sup.b are as
defined in formula I and R.sup.x may be the same or different and
is C.sub.1-6alkyl) and R.sup.9 is F may be prepared according to
Scheme 3
##STR00012##
[0399] Compounds of formula (VIa), (VIb) and (VIc) are commercially
available compounds, or they are known in the literature, or they
are prepared by standard processes known in the art.
[0400] In one aspect of the invention, there is provided a process
for preparing a compound of formula I which is a process selected
from Process a) and Process b).
[0401] It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples
of aromatic substitution reactions include the introduction of a
nitro group using concentrated nitric acid, the introduction of an
acyl group using, for example, an acyl halide and Lewis acid (such
as aluminium trichloride) under Friedel Crafts conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid
(such as aluminium trichloride) under Friedel Crafts conditions;
and the introduction of a halogeno group. Particular examples of
modifications include the reduction of a nitro group to an amino
group by for example, catalytic hydrogenation with a nickel
catalyst or treatment with iron in the presence of hydrochloric
acid with heating; oxidation of alkylthio to alkylsulphinyl or
alkylsulphonyl.
[0402] It will also be appreciated that in some of the reactions
mentioned herein it may be necessary/desirable to protect any
sensitive groups in the compounds. The instances where protection
is necessary or desirable and suitable methods for protection are
known to those skilled in the art. Conventional protecting groups
may be used in accordance with standard practice (for illustration
see T. W. Greene, Protective Groups in Organic Synthesis, John
Wiley and Sons, 1999). Thus, if reactants include groups such as
amino, carboxy or hydroxy it may be desirable to protect the group
in some of the reactions mentioned herein.
[0403] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a t-butoxycarbonyl group may be removed, for
example, by treatment with a suitable acid as hydrochloric,
sulphuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be
removed, for example, by hydrogenation over a catalyst such as
palladium-on-carbon, or by treatment with a Lewis acid for example
boron tris(trifluoroacetate). A suitable alternative protecting
group for a primary amino group is, for example, a phthaloyl group
which may be removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
[0404] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium or sodium hydroxide. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
[0405] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a t-butyl group which may
be removed, for example, by treatment with an acid, for example an
organic acid such as trifluoroacetic acid, or for example a benzyl
group which may be removed, for example, by hydrogenation over a
catalyst such as palladium-on-carbon.
[0406] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art.
[0407] The present invention also relates to intermediates for the
end products of the present invention. These intermediates are
useful in the preparation of a compound of formula I as defined
above. These intermediates are represented by, but not limited to,
the following [0408]
2-Chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine;
[0409] 2-Methyl-4-[(4-methylpiperazin-1-yl)carbonyl]aniline; [0410]
4-[(4-Methylpiperazin-1-yl)carbonyl]-3-nitroaniline; [0411]
4-[(4-Methylpiperazin-1-yl)carbonyl]-2-(trifluoromethoxy)aniline;
[0412]
4-[N-Acetyl-N-(tetrahydro-2H-pyran-4-yl)]amino-5-methylisoxazole;
[0413] 5-Acetyl-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole;
[0414]
(2E)-3-Dimethylamino-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-
-5-yl]prop-2-en-1-one; [0415]
(2Z)-3-Dimethylamino-2-fluoro-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-
-imidazol-5-yl]prop-2-en-1-one; [0416]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine; [0417]
1-(4-Chloro-2-methoxybenzoyl)-4-methylpiperazine; [0418]
1-[4-Bromo-2-(methylsulfonyl)benzoyl]-4-methylpiperazine; [0419]
4-(N-Acetyl-N-cyclohexyl)amino-5-methylisoxazole; [0420]
5-Acetyl-1-cyclohexyl-2-methyl-1H-imidazole; [0421]
(2E)-3-Dimethylamino-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)prop-2-en--
1-one; [0422]
(2Z)-3-Dimethylamino-2-fluoro-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)p-
rop-2-en-1-one; [0423]
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine;
[0424] 5-Acetyl-2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazole;
[0425]
(2E)-3-Dimethylamino-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-
-yl]prop-2-en-1-one; [0426]
(2Z)-3-Dimethylamino-2-fluoro-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-i-
midazol-5-yl]prop-2-en-1-one; [0427]
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]pyrimidi-
n-2-amine; [0428]
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine; [0429]
1-(tert-Butoxycarbonyl)-4-(4-bromo-benzenesulfonyl)-piperazine;
[0430]
5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-1H-imidazole;
[0431]
(2E)-3-Dimethylamino-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluorome-
thyl-1H-imidazol-5-yl]prop-2-en-1-one; [0432]
(2Z)-3-Dimethylamino-2-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluoro-
methyl-1H-imidazol-5-yl]prop-2-en-1-one; [0433]
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-amine; [0434]
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; [0435] 1-[(4-Bromo-2-chlorophenyl)sulfonyl]-4-methylpiperazine;
[0436] (3R)-4-[(4-Bromophenyl)sulfonyl]-3-methylmorpholine; [0437]
(1S,4S)-2-[(4-Bromophenyl)sulfonyl]-5-methyl-2,5-diazabicyclo[2.2.1]hepta-
ne; [0438] Methyl 4-bromo-2-(trifluoromethoxy)benzoate; [0439]
4-Bromo-2-(trifluoromethoxy)benzoic acid; [0440]
4-Bromo-2-(trifluoromethoxy)benzoic acid; [0441]
4-(4-Chloro-2-methylbenzyl)morpholine; [0442] Lithium
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate; [0443]
1-(4-Bromo-2-methylbenzoyl)azetidine; [0444]
4-Bromo-2-(trifluoromethoxy)benzoic acid; [0445]
1-[4-Bromo-2-(trifluoromethoxy)benzoyl]azetidine; [0446]
2,2,2-Trifluoro-N-methyl-N-(5-methylisoxazol-4-yl)acetamide; [0447]
1-[1-Methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]ethanone; [0448]
(2E)-3-(Dimethylamino)-1-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]p-
rop-2-en-1-one; [0449]
(2Z)-3-(Dimethylamino)-2-fluoro-1-[1-methyl-2-(trifluoromethyl)-1H-imidaz-
ol-5-yl]prop-2-en-1-one; [0450]
5-Fluoro-4-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; [0451] 4-[4-Bromo-2-(methylsulfonyl)benzyl]morpholine; [0452]
2-[(4-Bromophenyl)sulfonyl]ethyl methyl ether; [0453]
2-[(4-Bromophenyl)sulfonyl]ethyl diethyl-amine; [0454]
N-(5-Methyl-isoxazol-4-yl)-N-(tetrahydro-pyran-4-yl)-formamide;
[0455] 5-Acetyl-1-(tetrahydro-pyran-4-yl)-1H-imidazole; [0456]
(E)-3-Dimethylamino-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-propen-
one; [0457]
(Z)-3-Dimethylamino-2-fluoro-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-y-
l]-propenone; [0458]
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne; and [0459]
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimid
in-4-yl}-1-(tetrahydro-pyran-4-yl)-1H-imidazole-2-carbaldehyde.
General Methods
[0460] All solvents used were analytical grade and commercially
available anhydrous solvents were routinely used for reactions.
Reactions were typically run under an inert atmosphere of nitrogen
or argon.
[0461] .sup.1H, .sup.19F and .sup.13C NMR spectra were recorded on
a Varian Unity+400 NMR Spectrometer equipped with a 5 mm BBO
probehead with Z-gradients, or a Varian Gemini 300 NMR spectrometer
equipped with a 5 mm BBI probehead, or a Bruker Avance 400 NMR
spectrometer equipped with a 60 .mu.l dual inverse flow probehead
with Z-gradients, or a Bruker DPX400 NMR spectrometer equipped with
a 4-nucleus probehead equipped with Z-gradients, or a Bruker Avance
600 NMR spectrometer equipped with a 5 mm BBI probehead with
Z-gradients. Unless specifically noted in the examples, spectra
were recorded at 400 MHz for proton, 376 MHz for fluorine-19 and
100 MHz for carbon-13.
[0462] The following reference signals were used: the middle line
of DMSO-d.sub.6 .delta. 2.50 (1H), .delta. 39.51 (13C); the middle
line of CD.sub.3OD .delta. 3.31 (1H) or .delta. 49.15 (13C);
CDCl.sub.3 .delta. 7.26 (1H) and the middle line of CDCl.sub.3
.delta. 77.16 (13C) (unless otherwise indicated).
[0463] Mass spectra were recorded on a Waters LCMS consisting of an
Alliance 2795 (LC), Waters PDA 2996 and a ZQ single quadrupole mass
spectrometer. The mass spectrometer was equipped with an
electrospray ion source (ESI) operated in a positive or negative
ion mode. The capillary voltage was 3 kV and cone voltage was 30 V.
The mass spectrometer was scanned between m/z 100-700 with a scan
time of 0.3 s. Separations were performed on either Waters X-Terra
MS C8 (3.5 .mu.m, 50 or 100 mm.times.2.1 mm i.d.) or an ACE 3 AQ
(100 mm.times.2.1 mm i.d.) obtained from ScantecLab. Flow rates
were regulated to 1.0 or 0.3 mL/min, respectively. The column
temperature was set to +40.degree. C. A linear gradient was applied
using a neutral or acidic mobile phase system, starting at 100% A
(A: 95:5 10 mM NH.sub.4OAc:MeCN, or 95:5 8 mM HCOOH:MeCN) ending at
100% B (MeCN).
[0464] Alternatively, mass spectra were recorded on a Waters LCMS
consisting of an Alliance 2690 Separations Module, Waters 2487 Dual
1 Absorbance Detector (220 and 254 nm) and a Waters ZQ single
quadrupole mass spectrometer. The mass spectrometer was equipped
with an electrospray ion source (ESI) operated in a positive or
negative ion mode. The capillary voltage was 3 kV and cone voltage
was 30 V. The mass spectrometer was scanned between m/z 97-800 with
a scan time of 0.3 or 0.8 s. Separations were performed on a
Chromolith Performance RP-18e (100.times.4.6 mm). A linear gradient
was applied starting at 95% A (A: 0.1% HCOOH (aq.)) ending at 100%
B (MeCN) in 5 minutes. Flow rate: 2.0 mL/min.
[0465] Alternatively, compound identification was performed on a
GC-MS system (GC 6890, 5973N MSD) supplied by Agilent Technologies.
The column used was a VF-5 MS, ID 0.25 mm.times.15 m, 0.25 .mu.m
(Varian Inc.). A linear temperature gradient was applied starting
at 40.degree. C. (hold 1 min) and ending at +300.degree. C. (hold 1
min), +25.degree. C./minute. The mass spectrometer was equipped
with a chemial ionisation (CI) ion source and the reactant gas was
methane. The mass spectrometer was equipped with an electron impact
(EI) ion source and the electron voltage was set to 70 eV. The mass
spectrometer scanned between m/z 50-500 and the scan speed was set
to 3.25 scan/s.
[0466] Microwave heating was performed in a single-mode microwave
cavity producing continuous irradiation at 2450 MHz.
[0467] HPLC analyses were performed on an Agilent HPI000 system
consisting of G1379A Micro Vacuum Degasser, G1312A Binary Pump,
G1367A Well plate auto-sampler, G1316A Thermostatted Column
Compartment and G1315B Diode Array Detector. Column: X-Terra MS,
Waters, 3.0.times.100 mm, 3.5 .mu.m. The column temperature was set
to +40.degree. C. and the flow rate to 1.0 ml/min. The Diode Array
Detector was scanned from 210-300 nm, step and peak width were set
to 2 nm and 0.05 min, respectively. A linear gradient was applied,
starting at 100% A (A: 95:5 10 mM NH.sub.4OAc:MeCN) and ending at
100% B (B: MeCN), in 4 min.
[0468] Alternatively, HPLC analyses were performed on a Gynkotek
P580 HPG consisting of gradient pump with a Gynkotek UVD 170S
UV-vis.-detector equipped with a Chromolith Performance RP column
(C18, 100 mm.times.4.6 mm). The column temperature was set to
+25.degree. C. A linear gradient was applied using MeCN/0.1
trifluoroacetic acid in MilliQ water, run from 10% to 100% MeCN in
5 minutes. Flow rate: 3 ml/min.
[0469] A typical workup procedure after a reaction consisted of
extraction of the product with a solvent such as ethyl acetate,
washing with water followed by drying of the organic phase over
MgSO.sub.4 or Na.sub.2SO.sub.4, filtration and concentration of the
solution in vacuo.
[0470] Thin layer chromatography (TLC) was performed on Merck
TLC-plates (Silica gel 60 F.sub.254) and UV visualized the spots.
Flash chromatography was performed on a Combi Flash.RTM.
Companion.TM. using RediSep.TM. normal-phase flash columns or using
Merck Silica gel 60 (0.040-0.063 mm). Typical solvents used for
flash chromatography were mixtures of chloroform/methanol,
dichloromethane/methanol, heptane/ethyl acetate,
chloroform/methanol/ammonia (aq.) and
dichlorormethane/methanol/NH.sub.3 (aq.). SCX ion exchange columns
were performed on Isolute.RTM. columns. Chromatography through ion
exchange columns were typically performed in solvents such a
methanol.
[0471] Preparative chromatography was run on a Waters
autopurification HPLC with a diode array detector. Column: XTerra
MS C8, 19.times.300 mm, 10 .mu.m. Narrow gradients with MeCN/(95:5
0.1M NH.sub.4OAc:MeCN) were used at a flow rate of 20 ml/min.
Alternatively, purification was achieved on a semi preparative
Shimadzu LC-8A HPLC with a Shimadzu SPD-10A UV-vis.-detector
equipped with a Waters Symmetry.RTM. column (C18, 5 .mu.m, 100
mm.times.19 mm). Narrow gradients with MeCN/0.1% trifluoroacetic
acid in MilliQ Water were used at a flow rate of 10 m/min.
[0472] The formation of hydrochloride salts of the final products
were typically performed in solvents or solvents mixtures such as
diethyl ether, tetrahydrofuran, dichloromethane/toluene,
dichloromethane/methanol, followed by addition of 1M hydrogen
chloride in diethyl ether.
[0473] The following abbreviations have been used: [0474] aq.
aqueous; [0475] CHCl.sub.3. chloroform; [0476] CDCl.sub.3
deuterated chloroform; [0477] CD.sub.3OH deuterated methanol;
[0478] CH.sub.2Cl.sub.2 dichloromethane; [0479] Cs.sub.2CO.sub.3
caesium carbonate; [0480] DCM dichloromethane; [0481] DIPEA
N,N-diisopropylethylaamine; [0482] DMF N--N-dimethylformamide;
[0483] DMFDMA dimethylformamide dimethylacetal; [0484] DMSO
dimethyl sulphoxide; [0485] DMSO-d.sub.6 deuterated dimethyl
sulphoxide; [0486] dppp 1,3-bis(diphenylphosphino)propane; [0487]
EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; [0488] ether
diethyl ether; [0489] EtOAc ethyl acetate; [0490] EtOH ethanol;
[0491] H.sub.2 hydrogen gas; [0492] HCOOH acetic acid; [0493] HCl
hydrochloride; [0494] HOAc acetic acid; [0495] HOBt
1-hydroxybenzotriazole; [0496] (i-Pr).sub.2NEt
N--N-diisopropylethylamine; [0497] MeCN acetonitrile; [0498] MeI
methyl iodide; [0499] CD.sub.3OD deuterated methanol; [0500] MeOH
methanol; [0501] Me.sub.3SnCl trimethyltin chloride; [0502]
MgSO.sub.4 magnesium sulphate; [0503] NaBH.sub.3CN sodium
cyanoborohydride; [0504] NaHCO.sub.3 sodium bicarbonate; [0505]
NaOMe sodium methoxide; [0506] Na.sub.2SO.sub.4 sodium sulphate;
[0507] n-BuOH n-butanol; [0508] NH.sub.3 ammonia; [0509]
NH.sub.4OAc ammonium acetate; [0510] NH.sub.4OH ammonium hydroxide;
[0511] Pd/C palladium on carbon; [0512] Pd(PPh.sub.3).sub.2Cl.sub.2
bis(triphenylphosphine)palladium dichloride; [0513]
Pd(t-Bu.sub.3P).sub.2 bis(tri-tert-butylphosphine)palladium; [0514]
Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium; [0515]
Pd(OAc).sub.2 palladium diacetate; [0516] r.t. or RT room
temperature; [0517] Selectfluor
N-fluoro-N'-chloromethyl-triethylenediamine-bis(tetrafluoroborate);
[0518] t-BuLi tert-butyllithium; [0519] THF tetrahydrofuran; [0520]
X-Phos
2-dicyclohexylphosphino-2',4',6'-triiso-propyl-1,1'-biphenyl.
[0521] Starting materials used were either available from
commercial sources or prepared according to literature procedures
and had experimental data in accordance with those reported. The
following is an example of a starting material that was prepared:
(4-Bromophenyl)(pyridin-2-yl)methanone: Bruce, R. B. et al., J.
Med. Chem. 1968, 5, 1031-1034.
[0522] Compounds have been named either using ACD/Name, version
8.08, software from Advanced Chemistry Development, Inc.
(ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004 or using
Openeye lexichem version 1.4 (Copyright.COPYRGT. 1997-2006 OpenEye
Scientific Software, Santa Fe, N. Mex.) to generate the IUPAC
name.
[0523] In the following general methods A to I, the groups R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are used independently to indicate the
diversity of substitution within each structure. The identity of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 will be clear to a person
skilled in the art based on the starting materials and
intermediates for each specific example. For instance in Example
39, which refers to General method E, E1 is
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2--
amine such that R.sup.1 is tetrahydropyranyl, R.sup.3 is methyl and
R.sup.4 is hydrogen and E2 is 1-bromo-4-(methylsulfonyl)benzene
such that R.sup.2 is sulphonylmethane para to the halogen.
General Method A
##STR00013##
[0525] (i-Pr).sub.2NEt (2.1 equiv.), HOBt (1.05 equiv.), EDC
hydrochloride (1.05 equiv.) and the amine A2 (1.05 equiv.) were
added to a stirred solution of the benzoic acid A1 (1.0 equiv.) in
anhydrous DMF at r.t. After 15 h, the reaction mixture was poured
onto water and extracted with EtOAc. The organic layer was washed
with water and brine, dried Na.sub.2SO.sub.4), filtered and
evaporated in vacuo to afford the crude product, which was used in
the next step without further purification.
General Method B
##STR00014##
[0527] A reaction mixture of B1 (1.0 equiv.), guanidine
hydrochloride B2 (4.0 equiv.) and sodium methoxide (4.0 equiv.) in
1-butanol was heated in a microwave reactor for 10 minutes at
+140.degree. C. under argon or nitrogen atmosphere. The mixture was
filtered and the filter was rinsed with CH.sub.2Cl.sub.2. The
solvent was evaporated in vacuo and the crude product was purified
using flash column chromatography.
General Method C
##STR00015##
[0529]
2-Chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine C1
(1.0 equiv.), aniline C2 (1.1 equiv.) and sodium tert-butoxide (1.4
equiv.) were mixed in 1,4-dioxane and the mixture was flushed with
argon for 5 minutes. Pd(OAc).sub.2 (0.05 equiv.) and
Pd(t-Bu.sub.3P).sub.2 (0.05 equiv.) were added and the reaction was
stirred for 15 h at +110.degree. C. The solvent was removed in
vacuo and the residue was partitioned between EtOAc and water.
After extraction the organic layer was dried (MgSO.sub.4), filtered
and evaporated in vacuo to afford a crude material which was
purified by preparative HPLC.
General Method D
##STR00016##
[0531] D1 (1.0 equiv.), D2 (0.85-1.24 equiv.) and sodium
tert-butoxide (1.34-1.46 equiv.) were mixed in 1,4-dioxane and the
mixture was flushed with argon for 5-10 minutes before
Pd(OAc).sub.2 (0.04-0.082 equiv.) and Pd(t-Bu.sub.3P).sub.2
(0.044-0.06 equiv.) were added. The mixture was flushed with argon
then heated in a sealed tube at +110-+120.degree. C. until the
reaction was complete (as monitored by TLC or LC-MS). If the
reaction was not complete after 24 h more Pd(OAc).sub.2,
Pd(t-Bu.sub.3P).sub.2 and sodium tert-butoxide were added. The
solvent was removed in vacuo and the residue was partitioned
between CH.sub.2Cl.sub.2 and water. After extraction the organic
layer was dried (Na.sub.2SO.sub.4), filtered and evaporated. The
crude of the free base was purified using preparative HPLC. MeCN
was evaporated in vacuo and the aqueous phase was extracted with
CH.sub.2Cl.sub.2. The organic phase was washed with water at pH 9
(diluted NaHCO.sub.3 solution), dried (Na.sub.2SO.sub.4), filtered
and evaporated. The residue was dissolved in CH.sub.2Cl.sub.2 and
the HCl-adduct of the product was precipitated from the solution by
addition of 0.1M HCl in ether (1-5 equiv. HCl). The solvent was
evaporated and the residue was dissolved in water and freeze
dried.
General Method E
##STR00017##
[0533] E1 (0.85-1.27 equiv.), E2 (1.0 equiv.) and Cs.sub.2CO.sub.3
(1.29-2.25 equiv.) were mixed in anhydrous 1,4-dioxane and the
mixture was flushed with argon for 5-10 minutes before
Pd.sub.2(dba).sub.3 (0.02-0.08 equiv.) and X-Phos (0.04-0.16
equiv.) were added. The mixture was flushed with argon, then heated
in a sealed tube at +90-+100.degree. C. until the reaction was
complete.
[0534] Workup and purification was performed according to either
procedure A, B or C as follows. Procedure A) The solvent was
removed in vacuo and the residue was taken up in CH.sub.2Cl.sub.2
and washed with diluted NaHCO.sub.3 (aq.) or water. The organic
layer was dried (Na.sub.2SO.sub.4), filtered and evaporated. The
crude of the base product was purified using preparative HPLC.
Procedure B) The reaction mixture was diluted with H.sub.2O or a
mixture of H.sub.2O/CHCl.sub.3, the product was extracted with
CHCl.sub.3, the combined organic phases was, if needed, dried
(Na.sub.2SO.sub.4), filtered, concentrated and purified using flash
column chromatography. Procedure C) The reaction mixture was
diluted with CH.sub.2Cl.sub.2, filtered and evaporated. The residue
was taken up in CH.sub.2Cl.sub.2 and the organic phase was washed
with H.sub.2O. Residual water was removed from the organic phase
either by treatment with Na.sub.2SO.sub.4 or addition of absolute
EtOH before evaporation. The crude of the base product was is
purified using preparative HPLC.
[0535] Alternatively, the general example above was followed but
with a slight modification in the order of addition of reagents.
For example Cs.sub.2CO.sub.3 can be added together with E1 and E2
before the first argon flush.
General Method F
##STR00018##
[0537] F1 (1 equiv) was dissolved in CH.sub.2Cl.sub.2 (2 mL) and F2
(1.0-1.1 equiv) was added. The reaction mixture was stirred at room
temperature for 3 hours whereafter it was washed with saturated
NaHCO.sub.3 (2 mL). The organic phase was dried (Na.sub.2SO.sub.4),
filtered and concentrated to afford F3.
General Method G
##STR00019##
[0539] G1 (1.0 equiv.) and G2 (6.0 equiv.) was mixed in toluene
(1-4 mL) in a thick walled vial of 10 mL volume and an inert
atmosphere (Ar or N.sub.2) was established. The sealed vial was
cooled in an oil bath (r.t.) or in a dry-ice/ethanol bath
(-70.degree. C.) and Al(CH.sub.3).sub.3, (2M in toluene) (10
equiv.) was added by a syringe. The reaction mixture was heated in
an oil-bath at +90-100.degree. C. for 1-4 h, cooled to r.t., and
added dropwise into ice-cold sat. NaHCO.sub.3 (aq) under vigorous
stirring. The product was extracted with CH.sub.2Cl.sub.2 and the
organic layer was dried, either by treatment with Na.sub.2SO.sub.4
or addition of absolute EtOH before evaporation. The crude base of
the product was purified using flash column chromatography or
preparative HPLC.
General Method H
##STR00020##
[0541] Thionyl chloride (5 mL) was added to H1 (1.0 equiv.). After
addition of 2 drops of anhydrous DMF, the reaction mixture was
refluxed for 15-30 minutes under an atmosphere of nitrogen. The
solvent was evaporated in vacuo and the residue was dissolved in
CH.sub.2Cl.sub.2 (until a clear solution was obtained). H2 (1.0
equiv.) was added dropwise followed by addition of triethylamine
(1.0 equiv.). The reaction mixture was stirred at r.t. for 15-30
minutes before it was diluted with CH.sub.2Cl.sub.2, washed with
saturated NaHCO.sub.3 (aq.), dried (Na.sub.2SO.sub.4) and filtered.
The solvent was evaporated in vacuo and the crude product was
purified using flash column chromatography.
General Method I
##STR00021##
[0543] Sulfones of the type I3 were prepared following a modified
procedure from Richard W. Brown (J. Org. Chem. 1991, 56,
4974-4976). 4-Bromobenzenesulfonyl chloride (I1, 1 equiv.),
Na.sub.2SO.sub.3 (1 equiv.) and NaHCO.sub.3 (3 equiv.) in water
(0.2M) were stirred at +90.degree. C. for 1 hour. 12 (1-3 equiv.)
was then added and the resulting mixture stirred at +50-100.degree.
C. until the formation of the sulfone I3 was completed according to
GC-MS analysis. Water was added to the reaction mixture and
extracted with DCM. After extraction the organic layer was dried
(MgSO.sub.4), filtered and evaporated in vacuo to afford a crude
material which was purified by flash chromatography.
EXAMPLES
[0544] Below follows a number of non-limiting examples of compounds
of the invention.
Example 1
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[3-methoxy-5-(trifluoromethyl-
)phenyl]pyrimidin-2-amine
Example 1(a) 1,2-Dimethyl-5-(trimethylstannyl)-1N-imidazole
##STR00022##
[0546] 1,2-Dimethylimidazole (0.960 g, 10.0 mmol) was diluted in
dry THF (50 mL) under an argon atmosphere and the solution was
cooled to -78.degree. C. tert-Butyllithium (1.7M in pentane, 6.47
mL, 11.0 mmol) was added dropwise over 5 minutes. The reaction
mixture was stirred for 1 h at -78.degree. C. and then treated with
a solution of trimethyltin chloride (2.2 g, 11.0 mmol) in anhydrous
THF (10 mL). The mixture was stirred for 60 h from -78.degree. C.
to r.t. The solvent was then evaporated in vacuo to give the title
compound (1.29 g, 50%). The crude product was used in the next step
without further purification.
[0547] .sup.1H NMR (CDCl.sub.3) .delta. ppm 6.87 (s, 1H), 3.56 (s,
3H), 2.41 (s, 3H), 0.45-0.18 (m, 9H); MS (CI) m/z 261 (.sup.120Sn)
(M+1).
Example 1(b)
2-Chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine
##STR00023##
[0549] 1,2-Dimethyl-5-(trimethylstannyl)-1H-imidazole (0.950 g,
3.68 mmol, obtained from Example 1(a)) and
2,4-dichloro-5-fluoropyrimidine (0.601 g, 3.60 mmol) were diluted
in anhydrous DMF (20 mL) and the solution was degassed with argon.
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.126 g, 0.17 mmol) was added and the
reaction mixture was stirred at +80.degree. C. for 15 h. The
reaction mixture was cooled down to r.t. and concentrated under
reduced pressure. Saturated potassium fluoride (aq., 50 mL) was
added and the mixture was stirred for 30 minutes before extraction
with EtOAc. The organic layer was dried (MgSO.sub.4), filtered and
concentrated under reduced pressure. The crude product was purified
by flash chromatography (heptane/EtOAc, 7:3) to give the title
compound (0.41 g, 50%).
[0550] .sup.1H NMR (CDCl.sub.3, 600 MHz) .delta. ppm 8.40 (d, J=2.9
Hz, 1H), 7.86 (d, J=4.4 Hz, 1H), 3.97 (s, 3H), 2.53 (s, 3H); MS
(ESI) m/z 227 (M+1).
Example 1(c)
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[3-methoxy-5-(trifluoromethy-
l)phenyl]pyrimidin-2-amine
##STR00024##
[0552] The title compound was prepared in accordance with the
general method C using
2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine (50
mg, 0.221 mmol, obtained from Example 1(b)) and
3-methoxy-5-(trifluoromethyl)aniline (46 mg, 0.243 mmol) to give
the title compound (21 mg, 25%).
[0553] .sup.1H NMR (CDCl.sub.3) .delta. ppm 8.39-8.18 (m, 1H), 7.75
(d, J=4.3 Hz, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 7.14 (s, 1H), 6.81
(s, 1H), 4.00-3.89 (m, 3H), 3.85 (s, 3H), 2.49 (s, 3H);
[0554] .sup.19F NMR (376 MHz, CDCl.sub.3) .delta. ppm -63.16 (s,
3F), -144.69 (t, 1F); MS (ESI) m/z 382 (M+1).
Example 2
N-(3,5-Dichlorophenyl)-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-
-2-amine
##STR00025##
[0556] The title compound was prepared in accordance with the
general method C using
2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine
(obtained from Example 1(b)) (50 mg, 0.221 mmol) and
3,5-dichloroaniline (39 mg, 0.243 mmol) to give the title compound
(15 mg, 19%).
[0557] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 10.12 (s, 1H), 8.74
(d, J=2.8 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H),
7.72-7.55 (m, 1H), 7.16 (t, J=1.8 Hz, 1H), 4.00 (s, 3H), 2.57 (s,
3H); MS (ESI) m/z 352 (M+1).
Example 3
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}phenyl-
)(phenyl)methanone
##STR00026##
[0559] The title compound was prepared in accordance with the
general method C using
2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine
(obtained from Example 1(b)) (80 mg, 0.354 mmol) and
(4-aminophenyl)(phenyl)methanone (84 mg, 0.424 mmol), Pd(OAc).sub.2
(4.7 mg, 0.021 mmol) and Pd(t-Bu.sub.3P).sub.2 (10.7 mg, 0.021
mmol) to give the title compound (56 mg, 41%).
[0560] .sup.1H NMR (CDCl.sub.3) .delta. ppm 8.32 (s, 1H), 8.00-7.63
(m, 7H), 7.60-7.33 (m, 4H), 3.96 (s, 3H), 2.51 (s, 3H); MS (ESI)
m/z 388 (M+1).
Example 4
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{2-methyl-4-[(4-methylpiperaz-
in-1-yl)carbonyl]phenyl}pyrimidin-2-amine
Example 4(a)
2-Methyl-4-[(4-methylpiperazin-1-yl)carbonyl]aniline
##STR00027##
[0562] The title compound was prepared in accordance with the
general method A using N-methylpiperazine (0.44 mL, 4.0 mmol) and
4-amino-3-methylbenzoic acid (0.692 g, 3.8 mmol) to give the title
compound (0.421 g, 47%).
[0563] .sup.1H NMR (CDCl.sub.3) .delta. ppm 7.30 (s, 1H), 7.21 (s,
1H), 7.18-7.10 (m, 1H), 4.50-3.80 (br s, 4H), 3.91 (s, 3H),
3.20-2.50 (br s, 4H), 2.77 (m, 7H).
Example 4(b)
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{2-methyl-4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine
##STR00028##
[0565] The title compound was prepared in accordance with the
general method C using
2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine
(obtained from Example 11(b)) (50 mg, 0.221 mmol) and
2-methyl-4-[(4-methylpiperazin-1-yl)carbonyl]aniline (57 mg, 0.243
mmol) to give the title compound (15 mg, 16%).
[0566] .sup.1H NMR (CD.sub.3OD) .delta. ppm 8.31 (d, J=3.5 Hz, 1H),
7.70 (d, J=8.3 Hz, 1H), 7.63 (d, J=4.0 Hz, 1H), 7.35 (s, 1H), 7.29
(dd, J=8.2, 1.9 Hz, 1H), 3.83 (s, 3H), 3.79-3.42 (m, 4H), 2.63-2.47
(m, 4H), 2.45 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H); .sup.19F NMR
(CD.sub.3OD) .delta. ppm -151.35 (s, 1F); MS (ESI) m/z 424
(M+1).
Example 5
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)c-
arbonyl]-3-nitrophenyl}pyrimidin-2-amine
Example 5(a)
4-[(4-Methylpiperazin-1-yl)carbonyl]-3-nitroaniline
##STR00029##
[0568] The title compound was prepared in accordance with the
general method A using N-methylpiperazine (0.44 mL, 4.0 mmol) and
4-amino-2-nitrobenzoic acid (0.692 g, 3.8 mmol) to give the title
compound (0.531 g, 53%).
[0569] .sup.1H NMR (CD.sub.3OD) .delta. ppm 7.39 (d, J=2.3 Hz, 1H),
7.13 (d, J=8.1 Hz, 1H), 6.91 (dd, J=8.1, 2.3 Hz, 1H), 4.16 (s, 2H),
3.96 (s, 2H), 3.41 (s, 2H), 2.69 (s, 2H), 2.59-2.48 (m, 2H),
2.47-2.36 (m, 3H).
Example 5(b)
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)-
carbonyl]-3-nitrophenyl}pyrimidin-2-amine
##STR00030##
[0571] The title compound was prepared in accordance with the
general method C using
2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine
(obtained from Example 1(b)) (50 mg, 0.221 mmol) and
4-[(4-methylpiperazin-1-yl)carbonyl]-3-nitroaniline (64 mg, 0.243
mmol, obtained from Example 5(a)) to give the title compound (21
mg, 21%).
[0572] .sup.1H NMR (CD.sub.3OD) .delta. ppm 8.80 (d, J=2.0 Hz, 1H),
8.45 (d, J=3.3 Hz, 1H), 7.97 (dd, J=8.3, 2.1 Hz, 1H), 7.66 (d,
J=4.0 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 4.06 (s, 3H), 3.83 (s, 2H),
3.43-3.36 (m, 2H), 2.61 (t, J=5.2 Hz, 2H), 2.55-2.48 (s, 3H),
2.48-2.41 (m, 2H), 2.37 (s, 3H); .sup.19F NMR (CD.sub.3OD)
ppm-147.52 (s, 1F); MS (ESI) m/z 455 (M+1).
Example 6
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-[(4-methylpiperazin-1-yl)c-
arbonyl]-2-(trifluoromethoxy)phenyl]pyrimidin-2-amine
hydrochloride
Example 6(a)
4-[(4-Methylpiperazin-1-yl)carbonyl]-2-(trifluoromethoxy)aniline
##STR00031##
[0574] The title compound was prepared in accordance with the
general method A using N-methylpiperazine (0.44 mL, 4.0 mmol) and
4-amino-3-(trifluoromethyoxy)benzoic acid (0.840 g, 3.8 mmol) to
give the title compound (0.663 g, 57%).
[0575] .sup.1H NMR (CD.sub.3OD) .delta. ppm 7.33 (s, 1H), 7.25 (dd,
J=8.2, 1.9 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 4.21 (s, 2H), 3.96 (s,
4H), 3.16-2.33 (m, 7H).
Example 6(b)
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-[(4-methylpiperazin-1-yl)-
carbonyl]-2-(trifluoromethoxy)phenyl]pyrimidin-2-amine
hydrochloride
##STR00032##
[0577] The base of the title compound was prepared in accordance
with the general method C using
2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine
(obtained from Example 1(b)) (50 mg, 0.221 mmol) and
4-[(4-methylpiperazin-1-yl)carbonyl]-2-(trifluoromethoxy)aniline
(73 mg, 0.243 mmol, obtained from Example 6(a)). The hydrochloride
salt was obtained by dissolving the base product in anhydrous THF
(5 mL) and a solution of 1M HCl in ether (1 mL) was added. The
solvent was evaporated in vacuo and the residue was dried to give
the title compound (21 mg, 19%).
[0578] 1H NMR (CD.sub.3OD) .delta. ppm 8.62 (s, 1H), 8.23 (s, 1H),
8.13 (s, 1H), 7.57 (br s, 2H), 4.39 (s, 2H), 4.09 (s, 3H), 3.57 (s,
4H), 3.24 (s, 2H), 2.96 (s, 3H), 2.76 (s, 3H); .sup.19F NMR
(CD.sub.3OD) .delta. ppm-59.79 (s, 3F), -147.62 (s, 1F); MS (ESI)
m/z 494 (M+1).
Example 7
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
Example 7(a)
4-[N-Acetyl-N-(tetrahydro-2H-pyran-4-yl)]amino-5-methylisoxazole
##STR00033##
[0580] 5-Methyl-4-amino-isoxazole (Reiter, L. A., J. Org. Chem.
1987, 52, 2714-2726) (0.68 g, 5.1 mmol) and acetic acid (0.61 g,
10.2 mmol) were dissolved in MeOH (20 mL).
Tetrahydro-2H-pyran-4-one (0.76 g, 7.6 mmol) was added and the
mixture was cooled to 0-(-5).degree. C. and stirred for 1 h. Sodium
cyanoborohydride (0.32 g, 5.1 mmol) was added to is the reaction
mixture at -5.degree. C., causing weak exothermic and gas
evolution. The cooling bath was removed and the mixture was stirred
at r.t. for 1 h, followed by the addition of a second portion of
sodium cyanoborohydride (0.1 g, 1.6 mmol). After stirring for 2 h
at r.t., the mixture was filtered and the filtrate was concentrated
in vacuo. The residue was dissolved in toluene and re-concentrated.
The residue was dissolved in THF (10 mL) and acetic anhydride (1.56
g, 15.3 mmol) was added. The resulting mixture was stirred
overnight at r.t. then for 1 h at +50.degree. C. The volatiles were
removed in vacuo and the residue was dissolved in toluene and
concentrated in vacuo to give the title compound (1.36 g, 78%) as a
solid.
[0581] .sup.1H NMR (CDCl.sub.3) ppm .delta. 8.04 (s, 1H), 4.86-4.73
(m, 1H), 4.00-3.89 (m, 2H), 3.52-3.42 (m, 2H), 2.35 (s, 3H), 1.81
(s, 3H), 1.70-1.57 (m, 2H), 1.49-1.23 (m, 2H); MS (ESI) m/z 225
(M+1).
Example 7(b)
5-Acetyl-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole
##STR00034##
[0583] Sodium bicarbonate (0.8 g, 9.52 mmol) was added to a stirred
solution of
4-[N-acetyl-N-(tetrahydro-2H-pyran-4-yl)]amino-5-methylisoxazole
(4.8 g, 21.4 mmol, obtained from Example 7(a)) in EtOH (30 ml), and
the mixture was hydrogenated over Pd/C (10%, wet paste, 0.10 g) at
3 bar. The reaction mixture was stirred at +50.degree. C. for 3 h.
An additional amount of Pd/C (10%, wet paste, 0.15 g) was added and
the mixture was continued stirring at +50.degree. C. for 3 h.
Sodium methoxide (1.70 g, 31.46 mmol) was added and the resulting
mixture was heated to reflux for 30 h. Ammonium chloride was added
to quench the reaction. The mixture was filtrated through
diatomaceous earth and the filtrate was evaporated in vacuo. The
residue was diluted with saturated sodium bicarbonate (aq.) and
extracted with EtOAc, then with CHCl.sub.3. The combined organic
layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
crude product was purified by flash chromatography (EtOAc) to give
the title compound (3.7 g, 83%) as a yellow solid.
[0584] .sup.1H NMR (CDCl.sub.3) .delta. 7.70 (s, 1H), 5.40-5.30 (m,
1H), 4.13-4.01 (m, 2H), 3.57-3.44 (m, 2H), 2.57 (s, 3H), 2.44 (s,
3H), 2.43-2.30 (m, 2H), 1.80-1.72 (m, 2H).
Example 7(c)
(2E)-3-Dimethylamino-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-
-5-yl]prop-2-en-1-one
##STR00035##
[0586] 5-Acetyl-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazole
(3.7 g, 17.79 mmol, obtained 7(b)) was dissolved in DMFDMA/DMF
(1:1, 100 mL) and the mixture was stirred under reflux overnight.
After cooling to r.t. the mixture was extracted with
CH.sub.2Cl.sub.2. The organic phase was dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The crude product was purified
by flash chromatography (CH.sub.2Cl.sub.2/MeOH 15:1) to give the
title compound (3.85 g, 82%) as an oil that crystallized in the
refrigerator.
[0587] .sup.1H NMR (CDCl.sub.3) .delta. 7.65 (d, J=12.6 Hz, 1H),
7.46 (s, 1H), 5.55-5.42 (m, 2H), 4.08 (dd, J=11 Hz, 4.4 Hz, 2H),
3.52 (t, J=11 Hz, 2H), 2.99 (br s, 6H), 2.56 (s, 3H), 2.45-2.32 (m,
2H), 1.80-1.72 (m, 2H); MS (ESI) m/z 264 (M+1).
Example 7(d)
(2Z)-3-Dimethylamino-2-fluoro-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-
-imidazol-5-yl]prop-2-en-1-one
##STR00036##
[0589] Selectfluor (7.75 g, 21.87 mmol) was added in portions to a
stirred solution of
(2E)-3-dimethylamino-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-
-5-yl]prop-2-en-1-one (3.85 g, 14.58 mmol, obtained from Example
7(c)) in MeOH (100 mL) at r.t. After stirring at r.t. for 3 h the
reaction mixture was cooled in ice/acetone and filtered. The
filtrate was evaporated under reduced pressure and the residue was
taken into CH.sub.2Cl.sub.2. It was washed with aq. ammonia, brine,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude
product was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH
15:1). The reaction was not run to completion, and the reaction was
repeated again with Selectfluor (1.5 equiv.) followed by the same
workup. The title compound (1.47 g, 36%) was obtained as a yellow
oil.
[0590] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.34 (s, 1H), 6.84
(d, J=27.9 Hz, 1H), 5.00-4.88 (m, 1H), 4.04 (dd, J=11.2 Hz, 4.2 Hz,
2H), 3.46 (t, J=11 Hz, 2H), 3.08 (s, 6H), 2.53 (s, 3H), 2.42-2.28
(m, 2H), 1.84-1.75 (m, 2H); MS (ESI) m/z 282 (M.sup.++1).
Example 7(e)
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine
##STR00037##
[0592] The title compound was prepared in accordance with the
general method B with the exception that guanidine carbonate was
used. Using
(2Z)-3-dimethylamino-2-fluoro-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-
-imidazol-5-yl]prop-2-en-one (1.47 g, 5.22 mmol, obtained from
Example 7(d)) and guanidine carbonate (2.35 g, 13.06 mmol) the
title compound (1.21 g, 84%) was obtained as a solid after
purification by flash chromatography (CH.sub.2Cl.sub.2/MeOH
20:1).
[0593] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.17 (d, J=3.3 Hz,
1H), 7.59 (d, J=3.9 Hz, 1H), 5.27-5.13 (m, 1H), 4.93 (br s, 2H),
4.13 (dd, J=11.5 Hz, 4.3 Hz, 2H), 3.48 (t, J=11 Hz, 2H), 2.62 (s,
3H), 2.58-2.40 (m, 2H), 1.95-1.84 (m, 2H); MS (ESI) m/z 278
(M+1).
Example 7(f)
5-Fluoro-N-{4-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00038##
[0595] The title compound was prepared in accordance with the
general method D, with the exception that the base of the product
was purified by flash chromatography (CHCl.sub.3/MeOH/NH.sub.3 aq.
200:10:1) before purification by preparative HPLC. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (0.075 g, 0.27 mmol, obtained from Example 7(e)),
1-(4-bromo-benzenesulfonyl)-4-methylpiperazine (described in WO
2003004472) (0.108 g, 0.338 mmol), sodium tert-butoxide (0.036 g,
0.38 mmol), Pd(OAc).sub.2 (0.012 g, 0.054 mmol) and
Pd(t-Bu.sub.3P).sub.2 (0.14 g, 0.027 mmol), the title compound
(0.018 g, 11%) was obtained as a yellow solid.
[0596] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.64 (br s,
1H), 10.43 (s, 1H), 8.90 (s, 1H), 8.07 (s, 1H), 7.96 (d, J=8.4 Hz,
2H), 7.70 (d, J=8.4 Hz, 2H), 5.03-4.93 (m, 1H), 3.90-3.70 (m, 4H),
3.36-3.15 (m, 4H), 2.81 (s, 3H), 2.74 (s, 3H), 2.25-2.15 (m, 2H),
2.00-1.92 (m, 2H); MS (ESI) m/z 516 (M+1).
Example 8
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00039##
[0598] The title compound was prepared in accordance with the
general method D, with the exception that the base of the product
was purified by flash chromatography (CHCl.sub.3/MeOH/NH.sub.3 aq.
200:10:1) before purification by preparative HPLC. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (0.075 g, 0.27 mmol),
1-(4-bromobenzoyl)-4-methylpiperazine (0.115 g, 0.405 mmol), sodium
tert-butoxide (0.036 g, 0.38 mmol), Pd(OAc).sub.2 (0.012 g, 0.054
mmol) and Pd(t-Bu.sub.3P).sub.2 (0.14 g, 0.027 mmol), the base of
title compound (0.023 g, 18%) was obtained. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0599] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.02 (br s,
1H), 10.14 (s, 1H), 8.86 (s, 1H), 8.12 (s, 1H), 7.72 (d, J=8.1 Hz,
2H), 7.41 (d, J=8.1 Hz, 2H), 5.03-4.93 (m, 1H), 4.25-4.05 (m, 4H),
3.45-3.35 (m, 4H), 3.23-3.00 (m, 4H), 2.83 (s, 3H), 2.78 (s, 3H),
2.20-2.10 (m, 2H), 1.98-1.90 (m, 2H); MS (ESI) m/z 480 (M+1).
Example 9
5-Fluoro-N-{3-methoxy-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-met-
hyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
Example 9(a) 1-(4-Chloro-2-methoxybenzoyl)-4-methylpiperazine
##STR00040##
[0601] Thionyl chloride (5 mL) was added to
4-chloro-2-methoxybenzoic acid (0.501 g, 2.68 mmol). After addition
of 1 drop of anhydrous DMF, the reaction mixture was refluxed for
30 minutes under an atmosphere of nitrogen. The solvent was
evaporated in vacuo and the residue was dissolved in
CH.sub.2Cl.sub.2 (until a clear solution was obtained).
N-Methylpiperazine (0.31 nm, 2.81 mmol)) was added dropwise
followed by addition of triethylamine (0.39 mL, 2.81 mmol). The
reaction mixture was stirred at r.t. for 15 minutes before it was
diluted with CH.sub.2Cl.sub.2, washed with saturated NaHCO.sub.3
(aq.), water, dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo to give the title compound in quantitative yield. The
isolated material was used in the next step without further
purification.
[0602] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 7.18 (d, J=8.0 Hz,
1H), 7.17 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.0, 1.8 Hz, 1H), 3.81 (s,
3H), 3.67-3.51 (m, 2H), 3.14-3.04 (m, 2H), 2.38-2.27 (m, 2 H),
2.27-2.19 (m, 2H), 2.18 (s, 3H).
Example 9(b)
5-Fluoro-N-(3-methoxy-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl)-4-[2-me-
thyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00041##
[0604] The title compound was prepared in accordance with the
general method E, with the exception that the base of the product
was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH/NH.sub.3 aq. 200:10:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (0.075 g, 0.27 mmol),
1-(4-chloro-2-methoxybenzoyl)-4-methylpiperazine (0.065 g, 0.24
mmol, obtained from Example 9(a)), Cs.sub.2CO.sub.3 (176 mg, 0.54
mmol), Pd.sub.2(dba).sub.3 (12 mg, 0.013 mmol) and X-Phos (13 mg,
0.027 mmol), the base of the title compound (105 mg, 67%) was
obtained as a white solid. The hydrochloride of the title compound
was prepared in accordance with the general method D.
[0605] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.45 (br s,
1H), 10.08 (s, 1H), 8.85 (s, 1H), 8.13 (s, 1 H), 7.43 (d, J=7.8 Hz,
1H), 7.35 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 5.03-4.93 (m, 1H),
4.75-4.50 (m, 3H), 3.90-3.78 (m, 4H), 3.52-3.39 (m, 4H), 3.27-3.12
(m, 4H), 2.85 (s, 3H), 2.77 (s, 3H), 2.20-2.10 (m, 2H), 1.98-1.90
(m, 2H); MS (ESI) m/z 510 (M+1).
Example 10
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)carbonyl]-3-(methylsulfonyl)phenyl]-
-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne hydrochloride
Example 10(a)
1-[4-Bromo-2-(methylsulfonyl)benzoyl]-4-methylpiperazine
##STR00042##
[0607] Thionyl chloride (5 mL) was added to
4-bromo-2-(methylsulfonyl)benzoic acid (0.50 g, 1.67 mmol). After
addition of 1 drop of anhydrous DMF, the reaction mixture was
refluxed for 30 minutes under an atmosphere of nitrogen. The
solvent was evaporated in vacuo and the residue was dissolved in
CH.sub.2Cl.sub.2 (until a clear solution was obtained).
N-Methylpiperazine (0.195 mL, 1.75 mmol) was added dropwise
followed by addition of triethylamine (0.243 mL, 1.75 mmol). The
reaction mixture was stirred at r.t. for 15 minutes before it was
diluted with CH.sub.2Cl.sub.2, washed with saturated NaHCO.sub.3
(aq.), water, dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo to give the title compound in quantitative yield. The
isolated material was used in the next step without further
purification.
[0608] .sup.1H NMR (DMSO-d.sub.6, Signals corresponding to 3
protons were overlapping with the solvents) 5 ppm 8.06 (d, J=2.0
Hz, 1H), 8.01 (dd, J=8.3, 2.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),
3.65-3.53 (m, 2H), 3.19-3.00 (m, 2H), 2.43-2.33 (m, 2H), 2.33-2.21
(m, 2H), 2.19 (s, 3H); MS (ESI) m/z 361, 363 (M+1).
Example 10(b)
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)carbonyl]-3-(methylsulfonyl)phenyl-
]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-am-
ine hydrochloride
##STR00043##
[0610] The title compound was prepared in accordance with the
general method E, with the exception that the base of the product
was purified by flash chromatography (CHCl.sub.3/MeOH/NH.sub.3 aq.
200:10:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (67 mg, 0.242 mmol),
1-[4-bromo-2-(methylsulfonyl)benzoyl]-4-methylpiperazine (70 mg,
0.194 mmol, obtained from 10(a)), Cs.sub.2CO.sub.3 (71 mg, 0.22
mmol), Pd.sub.2(dba).sub.3 (11 mg, 0.012 mmol) and X-Phos (10 mg,
0.021 mmol), the base of the title compound (0.100 g, 92%) was
obtained as a solid. The hydrochloride of the title compound was
prepared in accordance with the general method D.
[0611] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.15 (br s,
1H), 10.41 (s, 1H), 8.91 (s, 1H), 8.30-8.25 (m, 1H), 8.20-8.11 (m,
2H), 7.55-7.49 (m, 1H), 5.01-4.88 (m, 1H), 4.70-4.50 (m, 1H),
3.95-3.62 (m, 6H), 3.59-3.44 (m, 2H), 3.40-3.08 (m, 7H), 2.84 (s,
3H), 2.81-2.75 (m, 3H), 2.23-2.11 (m, 2H), 2.01-1.94 (m, 2H); MS
(ESI) m/z 558 (M+1).
Example 11
5-Fluoro-N-[4-[(4-methylpiperazin-1-yl)sulfonyl]-3-(trifluoromethoxy)pheny-
l]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-a-
mine hydrochloride
##STR00044##
[0613] The title compound was prepared in accordance with the
general method E, with the exception that the base of the title
product was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH
20:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (32 mg, 0.116 mmol),
1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-4-methyl-piperazine
(described in WO 2003004472) (0.042 g, 0.104 mmol),
Cs.sub.2CO.sub.3 (38 mg, 0.12 mmol), Pd.sub.2(dba).sub.3 (6 mg,
0.006 mmol) and X-Phos (5 mg, 0.011 mmol), the base of the title
compound (38 mg, 61%) was obtained as a solid. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0614] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.31 (br s,
1H), 10.70 (s, 1H), 8.96 (s, 1H), 8.10 (s, 2H), 7.96 (d, J=9.0 Hz,
1H), 7.84 (d, J=9.0 Hz, 1H), 5.00-4.85 (m, 1H), 3.93-3.83 (m, 2H),
3.79-3.69 (m, 2H), 3.48-3.39 (m, 2H), 3.36-3.25 (m, 2H), 3.18-2.98
(m, 4H), 2.84 (s, 3H), 2.74 (s, 3H), 2.20-2.10 (m, 2H), 2.00-1.92
(m, 2H); MS (ESI) m/z 600 (M+1).
Example 12
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(-
pyrrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride
##STR00045##
[0616] The title compound was prepared in accordance with the
general method E, with the exception that the base of the title
product was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH
30:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.126 mmol),
1-(4-bromo-benzenesulfonyl)-pyrrolidine (33 mg, 0.113 mmol),
Cs.sub.2CO.sub.3 (41 mg, 0.13 mmol), Pd.sub.2(dba).sub.3 (6 mg,
0.007 mmol) and X-Phos (6 mg, 0.012 mmol), the base of the title
compound (54 mg, 98%) was obtained as a solid. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0617] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.37 (s, 1H),
8.89 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.89 (d, J=8.4 Hz, 2H),
7.72 (d, J=8.4 Hz, 2H), 5.03-4.93 (m, 1H), 3.87-3.78 (m, 2H),
3.29-3.07 (m, 6H), 2.83 (s, 3H), 2.22-2.12 (m, 2H), 2.00-1.92 (m,
2H), 2.64 (s, 4H); MS (ESI) m/z 487 (M+1).
Example 13
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(-
morpholin-4-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride
##STR00046##
[0619] The title compound was prepared in accordance with the
general method E, with the exception that the base of the title
product was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH
30:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (30 mg, 0.108 mmol),
4-(4-bromo-benzenesulfonyl)-morpholine (0.032 g, 0.103 mmol),
Cs.sub.2CO.sub.3 (38 mg, 0.116 mmol), Pd.sub.2(dba).sub.3 (6 mg,
0.006 mmol) and X-Phos (5 mg, 0.011 mmol), the base of the title
compound (52 mg, quantitative yield) was obtained as a solid. The
hydrochloride of the title compound was prepared in accordance with
the general method D.
[0620] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.41 (s, 1H),
8.90 (s, 1H), 8.10 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4
Hz, 2H), 5.03-4.91 (m, 1H), 3.88-3.78 (m, 2H), 3.62 (s, 4H),
3.29-3.14 (m, 2H), 2.85-2.81 (m, 7H), 2.23-2.12 (m, 2H), 2.00-1.92
(m, 2H); MS (ESI) m/z 503 (M+1).
Example 14
[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)phenyl](pyridin-2-yl)methanone hydrochloride
##STR00047##
[0622] The title compound was prepared in accordance with the
general method E, with the exception that the base of the title
product was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH
30:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.126 mmol),
(4-bromophenyl)(pyridin-2-yl)methanone (Bruce R. B. et al., J. Med.
Chem. 1968, 11, 1031-1034) (32 mg, 0.103 mmol), Cs.sub.2CO.sub.3
(44 mg, 0.13 mmol), Pd.sub.2(dba).sub.3 (6 mg, 0.007 mmol) and
X-Phos (6 mg, 0.013 mmol), the base of the title compound (53 mg,
96%) was given as a solid. The hydrochloride of the title compound
was prepared in accordance with the general method D.
[0623] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.40 (s, 1H),
8.90 (s, 1H), 8.73-8.68 (m, 1H), 8.14 (s, 1H), 8.10-7.89 (m, 4H),
7.82 (d, J=8.4 Hz, 2H), 7.69-7.63 (m, 1H), 5.07-4.94 (m, 1H),
3.88-3.80 (m, 2H), 3.26-3.14 (m, 2H), 2.85 (s, 3H), 2.22-2.11 (m,
2H), 2.01-1.93 (m, 2H); MS (ESI) m/z 459 (M+1).
Example 15
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(-
morpholin-4-ylmethyl)phenyl]pyrimidin-2-amine hydrochloride
##STR00048##
[0625] The title compound was prepared in accordance with the
general method E, with the exception that the reaction was heated
to +100.degree. C. for an additional 20 h, and the base of the
product was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH
15:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.126 mmol),
4-(4-bromobenzyl)-morpholine (0.031 g, 0.120 mmol),
Cs.sub.2CO.sub.3 (44 mg, 0.13 mmol), Pd.sub.2(dba).sub.3 (6 mg,
0.007 mmol) and X-Phos (6 mg, 0.013 mmol), the base of the title
compound (28 mg, 49%) was obtained as a solid. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0626] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.48 (br s,
1H), 10.07 (s, 1H), 8.83 (s, 1H), 8.09 (s, 1H), 7.69 (d, J=8.3 Hz,
2H), 7.54 (d, J=8.3 Hz, 2H), 5.03-4.91 (m, 1H), 4.25 (s, 2H),
3.96-3.76 (m, 6H), 3.25-3.12 (m, 4H), 3.10-2.97 (m, 2H), 2.83 (s,
3H), 2.22-2.11 (m, 2H), 2.00-1.90 (m, 2H); MS (ESI) m/z 453
(M+1).
Example 16
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(-
piperidin-1-ylcarbonyl)phenyl]pyrimidin-2-amine hydrochloride
##STR00049##
[0628] The title compound was prepared in accordance with the
general method E, with the exception that the base of the title
compound was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH 25:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.126 mmol),
1-(4-bromobenzoyl)piperidine (0.042 g, 0.157 mmol),
Cs.sub.2CO.sub.3 (46 mg, 0.14 mmol), Pd.sub.2(dba).sub.3 (7 mg,
0.008 mmol) and X-Phos (7 mg, 0.014 mmol), the base of the title
compound (52 mg, 89%) was obtained as a solid. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0629] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.05 (s, 1H),
8.83 (s, 1H), 8.08 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4
Hz, 2H), 5.05-4.94 (m, 1H), 3.85-3.77 (m, 2H), 3.50-3.32 (m, 4H),
3.21-3.09 (m, 2H), 2.82 (s, 3H), 2.19-2.10 (m, 2H), 1.96-1.88 (m,
2H), 1.63-1.58 (m, 2H), 1.54-1.42 (m, 4H); MS (ESI) m/z 465
(M+1).
Example 17
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperaz-
in-1-yl)carbonyl]phenyl}pyrimidin-2-amine hydrochloride
Example 17(a) 4-(N-Acetyl-N-cyclohexyl)amino-5-methylisoxazole
##STR00050##
[0631] The title compound was prepared in accordance with the
general method of Example 7 (a), with the exception that the
product was purified by flash chromatography (heptane/EtOAc 1:1).
Using 5-methyl-4-amino-isoxazole (Reiter, L. A, J. Org. Chem. 1987,
52, 2714-2726) (2.5 g, 25.48 mmol) and cyclohexanone (2.74 g, 28
mmol), the title compound was obtained (4.35 g, 77%) as a
solid.
[0632] MS (ESI) m/z 223 (M+1).
Example 17(b) 5-Acetyl-1-cyclohexyl-2-methyl-1H-imidazole
##STR00051##
[0634] The title compound was prepared in accordance with the
general method of Example 7(b), with the exception that the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH, 20:1).
Using 4-(N-acetyl-N-cyclohexyl)amino-5-methylisoxazole (4.35 g,
19.6 mmol, is obtained from Example 17(a)) the title compound was
obtained (1.2 g, 30%) as a yellow oil.
[0635] MS (ESI) m/z 207 (M+1).
Example 17(c)
(2E)-3-Dimethylamino-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)prop-2-en--
1-one
##STR00052##
[0637] The title compound was prepared in accordance with the
general method of Example 7 (c), with the exception that the
product was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH, 25:1). Using
5-acetyl-1-cyclohexyl-2-methyl-1H-imidazole (1.2 g, 5.80 mmol,
obtained from 17(b)) the title compound was obtained (1.4 g, 93%)
as an oil that solidified upon standing.
[0638] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.62 (d, J=12.6
Hz, 1H), 7.43 (s, 1H), 5.50 (d, J=12.6 Hz, 1H), 5.04-4.90 (m, 1H),
2.97 (br. s, 6H), 2.50 (s, 3H), 2.17-2.02 (m, 2H), 1.89-1.81 (m,
4H), 1.72-1.64 (m, 1H), 1.48-1.19 (m, 3H); MS (ESI) m/z 262
(M+1).
Example 17(d)
(2Z)-3-Dimethylamino-2-fluoro-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)p-
rop-2-en-1-one
##STR00053##
[0640] The title compound was prepared according to the general
method of Example 7 (d) with the following modification. The
reaction was repeated two times (first with 1.5 equiv. of
Selectfluor and then with 0.7 equiv.) in order to get full
conversion of the starting material. The product was purified by
flash chromatography (CH.sub.2Cl.sub.2/MeOH, 30:1 then 20:1) after
every treatment with Selectfluor. Starting from
(2E)-3-dimethylamino-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)prop-2-en--
1-one (1.39 g, 5.32 mmol, obtained from Example 17(c)) the title
compound was obtained (0.42 g, 28%).
[0641] MS (ESI) m/z 280 (M+1).
Example 17(e)
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
##STR00054##
[0643] The title compound was prepared in accordance with the
general method B with the exception that guanidine carbonate was
used. Using
(2Z)-3-dimethylamino-2-fluoro-1-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)p-
rop-2-en-one (0.42 g, 1.50 mmol, obtained from Example 17(d)) and
guanidine carbonate (0.68 g, 3.76 mmol) the title compound (0.35 g,
85%) was obtained as a white solid.
[0644] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.15 (d, J=3.3 Hz,
1H), 7.53 (d, J=3.9 Hz, 1H), 4.97-4.81 (m, 3H), 2.60 (s, 3H),
2.10-1.91 (m, 6H), 1.79-1.71 (m, 1H), 1.43-1.19 (m, 3H); MS (ESI)
m/z 276 (M+1).
Example 17(f)
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpipera-
zin-1-yl)carbonyl]phenyl}pyrimidin-2-amine hydrochloride
##STR00055##
[0646] The title compound was prepared in accordance with the
general method D, with the exception that the base of the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH
gradient; 20:1 to 10:1) before purification by preparative HPLC.
Using
4-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(0.075 g, 0.270 mmol, obtained from Example 17(e)),
1-(4-bromobenzoyl)-4-methylpiperazine (0.115 g, 0.405 mmol), sodium
tert-butoxide (0.036 g, 0.38 mmol), Pd(OAc).sub.2 (0.012 g, 0.054
mmol) and Pd(t-Bu.sub.3P).sub.2 (0.14 g, 0.027 mmol), the base of
the title compound (0.040 g, 31%) was obtained. The hydrochloride
of the title compound was prepared in accordance with the general
method D.
[0647] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.34 (br s,
1H), 10.18 (s, 1H), 8.85 (s, 1H), 8.11 (s, 1 H), 7.73 (d, J=8.4 Hz,
2H), 7.41 (d, J=8.4 Hz, 2H), 4.68-4.58 (m, 1H), 4.20-3.90 (m, 4H),
3.13-2.97 (m, 2H), 2.83 (s, 3H), 2.76 (s, 3H), 2.00-1.90 (m, 4H),
1.69-1.57 (m, 2H), 1.55-1.45 (m, 1H), 1.20-1.00 (m, 3H); MS (ESI)
m/z 478 (M+1).
Example 18
4-(1-Cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperaz-
in-1-yl)sulfonyl]phenyl}pyrimidin-2-amine hydrochloride
##STR00056##
[0649] The title compound was prepared in accordance with the
general method D, with the exception that the base of the product
was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH/NH.sub.3 aq. 200:10:1) before purification
by preparative HPLC. Using
4-(1-cyclohexyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(obtained from Example 17(e)) (0.075 g, 0.270 mmol),
1-(4-bromo-benzenesulfonyl)-4-methylpiperazine (described in WO
2003004472) (0.105 g, 0.320 mmol), sodium tert-butoxide (0.036 g,
0.38 mmol), Pd(OAc).sub.2 (0.012 g, 0.054 mmol) and
Pd(t-Bu.sub.3P).sub.2 (0.14 g, 0.027 mmol), the base of the title
compound (0.018 g, 14%) was obtained. The hydrochloride of the
title compound was prepared in accordance with the general method
D.
[0650] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.88 (br s,
1H), 10.48 (s, 1H), 8.90 (s, 1H), 8.10 (s, 1H), 7.96 (d, J=8.1 Hz,
2H), 7.68 (d, J=8.1 Hz, 2H), 4.69-4.59 (m, 1H), 3.76-3.66 (m, 2H),
3.19-3.05 (m, 2H), 2.82 (s, 3H), 2.73 (s, 3H), 2.02-1.85 (m, 4H),
1.70-1.60 (m, 2H), 1.55-1.48 (m, 1H), 1.25-1.02 (m, 3H); MS (ESI)
m/z 514 (M+1).
Example 19
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-{4-[(4-
-methylpiperazin-1-yl)carbonyl]phenyl}pyrimidin-2-amine
hydrochloride
Example 19(a)
5-Acetyl-2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazole
##STR00057##
[0652] The intermediate acetamide
(N-(1-aminopiperidin-4-yl)-N-isoxazol-4-ylacetamide) was prepared
in accordance with the general method of Example 7(a) starting from
5-methyl-4-amino-isoxazole (Reiter, L. A, J. Org. Chem., 1987, 52,
2714-2726) (0.61 g, 10.2 mmol), N-methylpiperidine-4-one (0.63 g,
5.6 mmol) and sodium cyanoborohydride (0.32 g, 5.1 mmol+0.1 g, 1.6
mmol). The title compound was prepared in accordance with the
general method of Example 7(b) using the crude intermediate
acetamide (N-(1-aminopiperidin-4-yl)-N-isoxazol-4-ylacetamide) to
give the title compound (0.40 g, 45%) after purification by flash
chromatography (CH.sub.2Cl.sub.2/MeOH/NH.sub.3 aq. 150:10:1).
[0653] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.85 (s, 1H),
5.28-5.16 (m, 1H), 3.02-2.92 (m, 2H), 2.56 (s, 3H), 2.43 (s, 3H),
2.40-2.24 (m, 5H), 2.19-2.06 (m, 2H), 1.86-1.76 (m, 2H);
[0654] MS (ESI) m/z 222 (M+1).
Example 19(b)
(2E)-3-Dimethylamino-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-
-yl]prop-2-en-1-one
##STR00058##
[0656] The title compound was prepared in accordance with the
general method of Example 7(c), using
5-acetyl-2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazole (2.1 g,
9.50 mmol, is obtained from Example 19(a)). After purification by
flash chromatography (CH.sub.2Cl.sub.2/MeOH/NH.sub.3 aq. gradient;
200:10:1 to 200:15:1.5) the title compound was obtained (1.92 g,
73%) as a yellow oil that solidified upon standing.
[0657] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.63 (d, J=12.3
Hz, 1H), 7.43 (s, 1H), 5.48 (d, J=12.3 Hz, 1H), 5.30-5.18 (m, 1H),
3.12-2.85 (m, 8H), 2.54 (s, 3H), 2.40-2.30 (m, 2H), 2.29 (s, 3H),
2.17-2.07 (m, 2H), 1.88-1.80 (m, 2H); MS (ESI) m/z 277 (M+1).
Example 19(c)
(2Z)-3-Dimethylamino-2-fluoro-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-i-
midazol-5-yl]prop-2-en-1-one
##STR00059##
[0659] Selectfluor (2.50 g, 6.95 mmol) was added in portions over 5
minutes to a stirred solution of
(2E)-3-dimethylamino-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-
-yl]prop-2-en-1-one (1.92 g, 6.95 mmol) in MeOH (30 mL) at
0.degree. C. After stirring for 90 minutes at r.t. more Selectfluor
(1.25 g, 3.5 mmol) was added and the mixture was stirred for 2
h.
[0660] When the reaction was complete it was concentrated in vacuo,
diluted with NH.sub.3 (3%, aq., 50 mL) and extracted with
CHCl.sub.3 (3.times.50 mL, contained 5% MeOH). The combined organic
phases were dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The crude product was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH/NH.sub.3 aq. 200:10:1), to give the title
compound (0.68 g, 33%) as an oil.
[0661] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.35 (s, 1H), 6.85
(d, J=27.3 Hz, 1H), 4.82-4.70 (m, 1H), 3.09 (s, 6H), 3.02-2.92 (m,
2H), 2.55 (s, 3H), 2.40-2.25 (m, 5H), 2.16-2.05 (m, 2H), 1.91-1.83
(m, 2H); MS (ESI) m/z 295 (M+1).
Example 19(d)
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]pyrimidi-
n-2-amine
##STR00060##
[0663] The title compound was prepared in accordance with the
general method B with the exception that guanidine carbonate was
used. Using
(2Z)-3-dimethylamino-2-fluoro-1-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-i-
midazol-5-yl]prop-2-en-1-one (0.68 g, 2.31 mmol, obtained from
Example 19(c)) and guanidine carbonate (1.05 g, 5.78 mmol) the
title compound was obtained (0.372 g, 55%) as a white solid after
purification by flash chromatography
(CH.sub.2Cl.sub.2/MeOH/NH.sub.3 aq. gradient; 200:10:1 to
100:10:1).
[0664] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.15 (d, J=3 Hz,
1H), 7.56 (d, J=3.6 Hz, 1H), 5.03-2.90 (m, 3H), 3.05-2.95 (m, 2H),
2.62 (s, 3H), 2.52-2.35 (m, 2H), 2.32 (s, 3H), 2.12-2.00 (m, 2H),
1.99-1.90 (m, 2H); MS (ESI) m/z 291 (M+1).
Example 19(e)
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-{4-[(-
4-methylpiperazin-1-yl)carbonyl]phenyl}pyrimidin-2-amine
hydrochloride
##STR00061##
[0666] The title compound was prepared in accordance with the
general method D, with the exception that the base of the product
was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH/NH.sub.3 aq., 500:30:3) before purification
by preparative HPLC. Using
5-fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]pyrimidi-
n-2-amine (0.075 g, 0.256 mmol, obtained from Example 19(d)),
1-(4-bromobenzoyl)-4-methylpiperazine (0.087 g, 0.307 mmol), sodium
tert-butoxide (0.036 g, 0.38 mmol), Pd(OAc).sub.2 (0.012 g, 0.054
mmol) and Pd(t-Bu.sub.3P).sub.2 (0.14 g, 0.027 mmol), the base of
the title compound was obtained (0.027 g, 21%). The hydrochloride
of the title compound was prepared in accordance with the general
method D.
[0667] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.31 (br s,
1H), 10.22 (s, 1H), 8.85 (s, 1H), 8.16 (s, 1H), 7.81 (d, J=8.1 Hz,
2H), 7.43 (d, J=8.1 Hz, 2H), 5.14-5.02 (m, 1H), 3.50-3.35 (m, 4H),
3.11-2.97 (m, 2H), 2.91 (s, 3H), 2.77 (s, 3H), 2.68 (s, 3H),
2.35-2.20 (m, 4H);
[0668] MS (ESI) m/z 493 (M+1).
Example 20
5-Fluoro-4-[2-methyl-1-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl]-N-[4-(py-
rrolidin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride
##STR00062##
[0670] The title compound was prepared in accordance with the
general method E, with the exception that the base of the product
was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH/NH.sub.3 aq. 200:10:1). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 19(d)) (40 mg, 0.136 mmol),
1-(4-bromo-benzenesulfonyl)-pyrrolidine (43 mg, 0.149 mmol),
Cs.sub.2CO.sub.3 (50 mg, 0.15 mmol), Pd.sub.2(dba).sub.3 (7 mg,
0.008 mmol) and X-Phos (7 mg, 0.015 mmol), the base of the title
compound (58 mg, 85%) was obtained as a solid. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0671] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.32 (br s,
1H), 10.48 (s, 1H), 8.89 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=8.1 Hz,
2H), 7.73 (d, J=8.1 Hz, 2H), 5.16-5.03 (m, 1H), 3.45-3.35 (m, 2H),
3.18-3.03 (m, 5H), 2.91 (s, 3H), 2.75-2.64 (m, 4H), 2.35-2.22 (m,
2H), 2.64 (s, 4H). MS (ESI) m/z 500 (M+1).
Example 21
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(-
trifluoromethyl)phenyl]pyrimidin-2-amine hydrochloride
##STR00063##
[0673] The title compound was prepared in accordance with the
general method E, with the exception that the base of the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH 40:1).
Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.126 mmol),
1-bromo-4-(trifluoromethyl)benzene (0.031 g, 0.139 mmol),
Cs.sub.2CO.sub.3 (92 mg, 0.28 mmol), Pd.sub.2(dba).sub.3 (7 mg,
0.008 mmol) and X-Phos (7 mg, 0.014 mmol), the base of the title
compound (50 mg, 92%) was obtained as a solid. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0674] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.28 (s, 1H),
8.87 (s, 1H), 8.10 (s, 1H), 7.84 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.1
Hz, 2H), 5.05-4.93 (m, 1H), 3.84-3.77 (m, 2H), 3.20-3.10 (m, 2H),
2.83 (s, 3H), 2.20-2.11 (m, 2H), 1.98-1.90 (m, 2H); MS (ESI) m/z
422 (M+1).
Example 22
5-Fluoro-N-[3-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-
-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride
##STR00064##
[0676] The title compound was prepared in accordance with the
general method E, with the exception that the base of the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH 25:1).
Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7 (e)) (35 mg, 0.126 mmol),
1-bromo-3-(methylsulfonyl)benzene (0.030 g, 0.126 mmol),
Cs.sub.2CO.sub.3 (92 mg, 0.28 mmol), Pd.sub.2(dba).sub.3 (7 mg,
0.008 mmol) and X-Phos (7 mg, 0.014 mmol), the base of the title
compound (44 mg, 81%) was obtained as a solid. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0677] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.19 (s, 1H),
8.86 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 8.01 (d, J=6.8 Hz, 1H),
7.62-7.52 (m, 2H), 5.03-4.91 (m, 1H), 3.87-3.79 (m, 2H), 3.24-3.10
(m, 5H), 2.82 (s, 3H), 2.20-2.10 (m, 2H), 1.97-1.90 (m, 2H). MS
(ESI) m/z 432 (M+1).
Example 23
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-
-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride
##STR00065##
[0679] The title compound was prepared in accordance with the
general method E, with the exception that the base of the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH 20:1).
Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.126 mmol),
1-chloro-4-(methylsulfonyl)benzene (0.0215 g, 0.113 mmol),
Cs.sub.2CO.sub.3 (92 mg, 0.28 mmol), Pd.sub.2(dba).sub.3 (7 mg,
0.008 mmol) and X-Phos (7 mg, 0.014 mmol), the base of the title
compound (45 mg, 94%) was obtained as a solid. The hydrochloride of
the title compound was prepared in accordance with the general
method D.
[0680] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.39 (s, 1H),
8.89 (s, 1H), 8.10 (s, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.6
Hz, 2H), 5.03-4.92 (m, 1H), 3.87-3.79 (m, 2H), 3.25-3.10 (m, 5H),
2.83 (s, 3H), 2.21-2.10 (m, 2H), 1.98-1.91 (m, 2H). MS (ESI) m/z
432 (M+1).
Example 24
3-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyr-
imidin-2-yl}amino)benzonitrile hydrochloride
##STR00066##
[0682] The title compound was prepared in accordance with the
general method E, with the exception that the base of the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH 40:1).
Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.126 mmol),
3-bromobenzonitrile (0.023 g, 0.126 ml-ol), Cs.sub.2CO.sub.3 (92
mg, 0.28 mmol), Pd.sub.2(dba).sub.3 (7 mg, 0.008 mmol) and X-Phos
(7 mg, 0.014 mmol), the base of the title compound (44 mg, 92%) was
obtained as a solid. The hydrochloride of the title compound was
prepared in accordance with the general method D.
[0683] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.22 (s, 1H),
8.87 (s, 1H), 8.18-8.05 (m, 2H), 7.90 (s, 1H), 7.55-7.25 (m, 2H),
5.03-4.91 (m, 1H), 3.85-3.77 (m, 2H), 3.22-3.10 (m, 2H), 2.83 (s,
3H), 2.21-2.11 (m, 2H), 1.97-1.90 (m, 2H). MS (ESI) m/z 379
(M+1).
Example 25
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(morpholin-4-ylmethyl)phen-
yl]pyrimidin-2-amine hydrochloride
Example 25(a)
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
##STR00067##
[0685]
2-Chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine
(0.295 g, 1.30 mmol) (obtained from Example 1(b)) was dissolved in
1-propanol (3.0 mL) in a microwave vial. Ammonium hydroxide (28%,
1.0 mL) was added, the vial was sealed and the mixture heated in a
microwave oven (+140.degree. C., 4 h). The reaction mixture was
cooled to r.t. and the solvent was evaporated. The residue was
partitioned between CH.sub.2Cl.sub.2 and 1M aqueous HCl. The
aqueous phase, containing the product, was neutralized with
saturated aqueous NaHCO.sub.3 and the product extracted with
CH.sub.2Cl.sub.2. The organic phase was co-evaporated with ethanol
and the residue was purified by flash chromatography using
(CH.sub.2Cl.sub.2/MeOH gradient; 100:1 to 94:6) to give the title
compound (0.210 g, 78%) as a solid.
[0686] .sup.1H NMR (CDCl.sub.3) .delta. ppm 8.15 (d, J=3.5 Hz, 1H),
7.71 (d, J=4.3 Hz, 1H), 4.87 (br s, 2H), 3.97 (s, 3H), 2.49 (s,
3H); MS (ESI) m/z 208 (M+1).
Example 25(b)
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(morpholin-4-ylmethyl)phe-
nyl]pyrimidin-2-amine hydrochloride
##STR00068##
[0688] The title compound was prepared in accordance with the
general method E. Using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine (21 mg,
0.10 mmol, obtained from Example 25(a)),
4-(4-bromobenzyl)morpholine (28 mg, 0.11 mmol), Cs.sub.2CO.sub.3
(58 mg, 0.18 mmol), Pd.sub.2(dba).sub.3 (7 mg, 0.007 mmol) and
X-Phos (8 mg, 0.017 mmol), the base of the title compound was
obtained as a solid. The hydrochloride of the title compound was
prepared in accordance with the general method D, with the
exceptions that dilute ammonium hydroxide was used instead of
dilute NaHCO.sub.3 in the washing of the organic phase. The organic
phase was co-evaporated with absolute ethanol instead of drying
with Na.sub.2SO.sub.4 before evaporation, and the precipitated salt
was collected by filtration and re-dissolved in water before freeze
drying, giving the title compound (28 mg, 61%) as a yellow
solid.
[0689] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 10.84 (br s, 1H),
10.02 (s, 1H), 8.75 (d, J=2.5 Hz, 1H), 8.15 (d, J=2.5 Hz, 1H), 7.75
(d, J=8.5 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 4.26 (s, 2H), 4.01 (s,
3H), 3.99-3.86 (m, 2H), 3.76 (t, J=11.8 Hz, 2H), 3.25-3.14 (m, 2H),
3.13-2.96 (m, 2H), 2.66 (s, 3H); MS (ESI) m/z 381 (M+1).
Example 26
4-(1,2-Dimethyl-If-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)s-
ulfonyl]phenyl}pyrimidin-2-amine
##STR00069##
[0691] The title compound was prepared in accordance with the
general method E. Using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(obtained from Example 25(a)) (23 mg, 0.11 mmol),
1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (37 mg, 0.11 mmol),
Cs.sub.2CO.sub.3 (59 mg, 0.18 mmol), Pd.sub.2(dba).sub.3 (6 mg,
0.006 mmol) and X-Phos (6 mg, 0.013 mmol), the base of the title
compound was obtained as a solid. The hydrochloride of the title
compound was prepared in accordance with the procedure described in
Example 25 (b), giving the title compound (33 mg, 57%) as a yellow
solid.
[0692] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 10.44 (br s, 1H),
10.42 (s, 1H), 8.82 (d, J=2.5 Hz, 1H), 8.13 (br s, 1H), 7.99 (d,
J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 4.03 (s, 3H), 3.83-3.63 (m,
2H), 3.23-3.02 (m, 4H), 2.74 (s, 3H), 2.65 (s, 3H), 2.70-2.56 (m,
2H); MS (ESI) m/z 446 (M+1).
Example 27
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(piperidin-1-ylcarbonyl)ph-
enyl]pyrimidin-2-amine hydrochloride
##STR00070##
[0694] The title compound was prepared in accordance with the
general method E. Using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(obtained from Example 25 (a)) (25 mg, 0.12 mmol),
1-(4-bromobenzoyl)piperidine (33 mg, 0.12 mmol), Cs.sub.2CO.sub.3
(66 mg, 0.20 mmol), Pd.sub.2(dba).sub.3 (6 mg, 0.007 mmol) and
X-Phos (6 mg, 0.013 mmol), the base of the title compound was
obtained as a solid. The hydrochloride of the title compound was
prepared in accordance with the procedure described in Example
25(b), giving the title compound (35 mg, 61%) as a white solid.
[0695] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 10.04 (s, 1H), 8.77
(d, J=2.8 Hz, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H),
7.35 (d, J=8.8 Hz, 2H), 4.02 (s, 3H), 3.50-3.41 (m, 4H), 2.66 (s,
3H), 1.67-1.57 (m, 2H), 1.57-1.42 (m, 4H); MS (ESI) m/z 395
(M+1).
Example 28
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)c-
arbonyl]phenyl}pyrimidin-2-amine hydrochloride
##STR00071##
[0697] The title compound was prepared in accordance with the
general method E. Using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(obtained from Example 25(a)) (18 mg, 0.089 mmol),
1-(4-bromobenzoyl)-4-methylpiperazine (25 mg, 0.089 mmol),
Cs.sub.2CO.sub.3 (42 mg, 0.13 mmol), Pd.sub.2(dba).sub.3 (4 mg,
0.004 mmol) and X-Phos (4 mg, 0.009 mmol), the base of the title
compound was obtained as a solid. The hydrochloride of the title
compound was prepared in accordance with the procedure described in
Example 25 (b), giving the title compound (28 mg, 64%) as a yellow
solid.
[0698] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 10.71 (br s, 1H),
10.13 (s, 1H), 8.78 (d, J=2.8 Hz, 1H), 8.18 (d, J=2.5 Hz, 1H), 7.78
(d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 4.20 (br s, 2H), 4.03
(s, 3H), 3.07 (br s, 2H), 2.79 (s, 3H), 2.67 (s, 3H); MS (ESI) m/z
410 (M+1).
Example 29
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{4-[(4-methylpiperazin-1-yl)m-
ethyl]phenyl}pyrimidin-2-amine hydrochloride
##STR00072##
[0700] The title compound was prepared in accordance with the
general method E. Using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(obtained from Example 25 (a)) (19 mg, 0.091 mmol),
1-(4-bromobenzyl)-4-methylpiperazine (Organ, M. G. et al, J. Comb.
Chem. 2001, 3, 473-476) (28 mg, 0.10 mmol), Cs.sub.2CO.sub.3 (42
mg, 0.13 mmol), Pd.sub.2(dba).sub.3 (5 mg, 0.005 mmol) and X-Phos
(4 mg, 0.009 mmol), the base of the title compound was obtained as
a solid. The hydrochloride of the title compound was prepared in
accordance with the procedure described in Example 25 (b), giving
the title compound (28 mg, 61%) as a yellow solid.
[0701] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 10.00 (br s, 1H),
8.76 (d, J=2.5 Hz, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.72 (d, J=8.3 Hz,
2H), 7.55-7.38 (m, 2H), 4.02 (s, 3H), 4.02 (br s, 1H), 2.79 (s, 3
H), 2.68 (s, 3H); MS (ESI) m/z 396 (M+1).
Example 30
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-[(4-methylpiperazin-1-yl)c-
arbonyl]phenyl}pyrimidin-2-amine hydrochloride
##STR00073##
[0703] The title compound was prepared in accordance with the
general method E. Using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(obtained from Example 25 (a)) (18 mg, 0.084 mmol),
1-(3-chlorobenzoyl)-4-methylpiperazine (21 mg, 0.87 mmol),
Cs.sub.2CO.sub.3 (43 mg, 0.13 mmol), Pd.sub.2(dba).sub.3 (4 mg,
0.004 mmol) and X-Phos (4 mg, 0.009 mmol), the base of the title
compound was obtained as a solid. The hydrochloride of the title
compound was prepared in accordance with the procedure described in
Example 25 (b), giving the title compound (13 mg, 32%) as a yellow
solid.
[0704] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 10.69 (br s, 1H),
10.00 (s, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.12 (br s, 1H), 7.83-7.72
(m, 2H), 7.42 (t, J=7.9 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 4.50 (br
s, 1H), 4.01 (s, 3H), 2.80 (s, 3H), 2.65 (s, 3H); MS (ESI) m/z 410
(M+1).
Example 31
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}phenyl-
)(pyridin-2-yl)methanone hydrochloride
##STR00074##
[0706] The title compound was prepared in accordance with the
general method E. Using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(obtained from Example 25(a)) (23 mg, 0.11 mmol),
(4-bromophenyl)(pyridin-2-yl)methanone (29 mg, 0.11 mmol),
Cs.sub.2CO.sub.3 (72 mg, 0.22 mmol), Pd.sub.2(dba).sub.3 (6 mg,
0.007 mmol) and X-Phos (7 mg, 0.016 mmol), the base of the title
compound was obtained as a solid. The hydrochloride of the title
compound was prepared in accordance with the procedure described in
Example 25(b), giving the title compound (28 mg, this compound
appeared to be a non-stoichiometric salt, gives an estimated yield
of 55%) as a yellow solid.
[0707] .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 10.36 (s, 1H), 8.84
(d, J=2.5 Hz, 1H), 8.75-8.69 (m, 1H), 8.20 (d, J=2.8 Hz, 1H),
8.09-8.00 (m, 3H), 7.92 (d, J=7.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H),
7.68-7.62 (m, 1H), 4.04 (s, 3H), 2.67 (s, 3H); MS (ESI) m/z 389
(M+1).
Example 32
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyr-
imidin-2-yl}amino)benzonitrile hydrochloride
##STR00075##
[0709] The title compound was prepared in accordance with the
general method E, with the exception that the base of the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH 30:1).
Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.126 mmol),
4-chlorobenzonitrile (15.5 g, 0.113 mmol), Cs.sub.2CO.sub.3 (92 mg,
0.28 mmol), Pd.sub.2(dba).sub.3 (7 mg, 0.008 mmol) and X-Phos (7
mg, 0.014 mmol), the base of the title compound (38 mg, 88%) was
obtained as a solid. The hydrochloride of the title compound was
prepared in accordance with the general method D.
[0710] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.42 (s, 1H),
8.90 (s, 1H), 8.09 (s, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5
Hz, 2H), 5.04-4.92 (m, 1H), 3.89-3.81 (m, 2H), 3.26-3.16 (m, 2H),
2.83 (s, 3H), 2.20-2.12 (m, 2H), 1.97-1.90 (m, 2H); MS (ESI) m/z
379 (M+1).
Example 33
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(-
piperazin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride
Example 33(a)
1-(tert-Butoxycarbonyl)-4-(4-bromo-benzenesulfonyl)-piperazine
##STR00076##
[0712] N-boc-piperazine (0.5 g, 2.68 mmol) and diisopropyethylamine
(0.69 g, 5.36 mmol) were dissolved in CH.sub.2Cl.sub.2 (50 mL) and
cooled to 0.degree. C. 4-Bromo-phenylsulphonyl chloride (0.68 g,
2.68 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added dropwise under
vigorous stirring. After stirring for 15 h at r.t. the reaction
mixture was washed with saturated aqueous NaHCO.sub.3 (2.times.20
mL), brine, then dried (Na.sub.2SO.sub.4) and concentrated to
dryness. The solid residue was recrystallized from heptane/EtOAc
mixture (2:1), filtered and washed with cold heptane. The title
compound was obtained (0.8 g, 74%) as a white solid.
[0713] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.68 (d, J=8.4 Hz,
2H), 7.61 (d, J=8.4 Hz, 2H), 3.54-3.47 (m, 4H), 3.01-2.94 (m, 4H),
1.41 (s, 9H).
Example 33(b)
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4--
(piperazin-1-ylsulfonyl)phenyl]pyrimidin-2-amine hydrochloride
##STR00077##
[0715]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-
pyrimidin-2-amine (obtained from Example 7(e)) (45 mg, 0.162 mmol)
and 1-(tert-butoxycarbonyl)-4-(4-bromo-benzenesulfonyl)-piperazine
(62 mg, 0.154 mmol) were dissolved in dioxane (3 mL). Cesium
carbonate (105 mg, 0.324 mmol) was added and nitrogen gas was
bubbled throw the stirred suspension for 2-3 min followed by the
addition of Pd.sub.2(dba).sub.3 (7.5 mg, 0.0081 mmol) and X-Phos
(7.7 g, 0.0162 mmol). The vessel was closed and heated to
+90.degree. C. and stirred at this temperature for 20 h. The cooled
mixture was diluted with chloroform (15 ml) and water (20 mL), the
aqueous layer was separated and extracted with chloroform (20 mL).
The combined organic layers were dried (Na.sub.2SO.sub.4) and the
solvent was removed in vacuo. The residue was purified by flash
chromatography using CH.sub.2Cl.sub.2/MeOH (40:1) as eluent.
Product-containing fractions were concentrated, dissolved in MeOH
(20 mL) and treated with HCl (37% aqueous, 0.5 mL). The mixture was
stirred overnight at r.t. and concentrated to dryness. Diluted with
chloroform (20 mL) and water (20 mL) and the aqueous layer was
separated and extracted with chloroform (3.times.20 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4), the solvents
were removed in vacuo and the residue was purified by flash
chromatography using CH.sub.2Cl.sub.2/MeOH/aqueous NH.sub.3
(150:10:1 to 100:10:1) as eluent, obtaining the base (22 mg, 28%)
as an oil. The base of the title compound was dissolved in
chloroform/ether (1:1) and treated with 1M HCl in ether. The
resulting precipitate was collected by filtration and washed with
ether to obtain of the title compound (13 mg) as a solid.
[0716] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.45 (s, 1H),
9.12 (br s, 1H), 8.90 (s, 1H), 8.07 (s, 1H), 7.96 (d, J=8.7 Hz,
2H), 7.70 (d, J=8.7 Hz, 2H), 5.03-4.93 (m, 1H), 3.89-3.81 (m, 2H),
3.65-3.40 (m, 2H), 3.28-3.09 (m, 8H), 2.82 (s, 3H), 2.22-2.10 (m,
2H), 2.00-1.92 (m, 2H); MS (ES) m/z 502 (M+1).
Example 34
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[1-(tetrahydro-2-
H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
Example 34(a)
5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-1H-imidazole
##STR00078##
[0718] 5-Methyl-4-amino-isoxazole (1.7 g, 17.25 mmol) and acetic
acid (1.1 g, 19 mmol) were dissolved in methanol (50 mL).
Tetrahydro-2H-pyran-4-one (1.9 g, 19 mmol) was added and the
mixture was cooled to 0-(-5).degree. C. and stirred for 1 h. Sodium
cyanoborohydride (0.812 g, 12.9 mmol) was added in portions to the
reaction mixture at -5.degree. C., causing weak exothermic and gas
evolution. The cooling bath was removed and the mixture was stirred
at r.t. for 2 h followed by addition of water (20 mL). The methanol
was removed from the reaction mixture by vacuum distillation, and
the intermediate amine was extracted with ethyl acetate (3.times.80
mL). The combined organic layers were dried (Na.sub.2SO.sub.4),
concentrated to dryness, dissolved in toluene and re-concentrated.
The crude intermediate amine, was dissolved in CH.sub.2Cl.sub.2 (20
mL) and pyridine (2 mL, 26 mmol) was added. The mixture was cooled
to 0.degree. C. and trifluoroacetic anhydride (4.35 g, 20.7 mmol)
was added dropwise. The mixture was continued stirring for 2 h at
r.t. then washed with water and saturated NaHCO.sub.3. The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.30 mL), the
organic extracts were dried (Na.sub.2SO.sub.4) and concentrated to
dryness to give a second crude intermediate,
4-[N-(tetrahydro-2H-pyran-4-yl)]-N-trifluoroacetyl-amino-5-methylisoxazol-
e. MS (ES) m/z 279 (M.sup.++1). The title compound was prepared in
accordance with the general method of Example 7 (b) using the
intermediate
4-[N-(tetrahydro-2H-pyran-4-yl)]-N-trifluoroacetyl-amino-5-methylisoxazol-
e (max 17.25 mmol), with the exception that the product was
purified by flash chromatography (heptane/EtOAc 3:2), giving the
title compound (3.03 g, 67%) as an oil.
[0719] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.85 (s, 1H),
4.89-4.75 (m, 1H), 4.17-4.07 (m, 2H), 3.54-3.44 (m, 2H), 2.75-2.60
(m, 2H), 2.56 (s, 3H), 1.72-1.63 (m, 2H);
[0720] MS (ES) m/z 263 (M+1).
(b)
(2E)-3-Dimethylamino-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-
-1H-imidazol-5-yl]prop-2-en-1-one
##STR00079##
[0722] The title compound was prepared in accordance with the
general method of Example 7 (c), with the exception that the
product was purified by flash chromatography (EtOAc). Using
5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-1H-imidazole
(3.03 g, 11.55 mmol, obtained from Example 34(a)) the title
compound was obtained (3.2 g, 87%) as an oil.
[0723] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.72 (d, J=12.3
Hz, 1H), 7.49 (s, 1H), 5.50 (d, J=12.3 Hz, 1H), 4.89-4.75 (m, 1H),
4.14-4.05 (m, 2H), 3.54-3.44 (m, 2H), 3.16 (br. s, 3H), 2.93 (br.
s, 3H), 2.86-2.72 (m, 2H), 1.80-1.72 (m, 2H); MS (ES) m/z 318
(M+1).
Example 34(c)
(2Z)-3-Dimethylamino-2-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluoro-
methyl-1H-imidazol-5-yl]prop-2-en-1-one
##STR00080##
[0725] Selectfluor (0.370 g, 1.04 mmol) was added in portions to a
stirred solution of
(2E)-3-dimethylamino-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl-1H-
-imidazol-5-yl]prop-2-en-1-one (0.300 g, 0.946 mmol, obtained from
Example 34(b)) in MeCN (20 mL) at 0.degree. C. After stirring for
0.5 h at r.t. more Selectfluor (0.050 g, 0.14 mmol) was added, and
the mixture was stirred for 0.5 h. The solvent was evaporated in
vacuo, diluted with 3% aqueous NH.sub.3 (20 mL) and extracted with
CHCl.sub.3 (3.times.20 mL). The organic extracts were dried
(Na.sub.2SO.sub.4), evaporated in vacuo and the crude product was
purified by flash chromatography (heptane/EtOAc 1:2), followed by
neat EtOAc) to obtain the title compound (0.170 g, 53%) as an
oil.
[0726] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.34 (s, 1H), 6.85
(d, J=26.7 Hz, 1H), 4.67-4.54 (m, 1H), 4.11-4.03 (m, 2H), 3.50-3.38
(m, 2H), 3.14 (s, 6H), 2.72-2.56 (m, 2H), 1.83-1.74 (m, 2H);
[0727] MS (ES) m/z 336 (M+1).
Example 34(d)
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-amine
##STR00081##
[0729] The title compound was prepared in accordance with the
general method B with the exception that guanidine carbonate was
used. Using
(2Z)-3-dimethylamino-2-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-2-trifluoro-
methyl-1H-imidazol-5-yl]prop-2-en-1-one (0.330 g, 1.0 mmol,
obtained from Example 34(c)) and guanidine carbonate (0.45 g, 2.50
mmol). After purification by flash chromatography (heptane/EtOAc
1:2), the title compound was obtained (0.170 g, 51%) as a white
solid.
[0730] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.29 (s, 1H), 7.63
(d, J=2.7 Hz, 1H), 5.10 (br.s., 2H), 4.88-4.76 (m, 1H), 4.16-4.07
(m, 2H), 3.53-3.42 (m, 2H), 2.80-2.65 (m, 2H), 1.89-1.81 (m, 2H);
MS (ES) m/z 332 (M+1).
Example 34(e)
5-Fluoro-N-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[1-(tetrahydro--
2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00082##
[0732] The title compound was prepared in accordance with the
general method of Example 33(b). Using
5-fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-amine (33 mg, 0.100 mmol, obtained from Example
34(d)) and 1-(4-bromo-benzenesulfonyl)-4-methylpiperazine
(described in WO 2003004472) (29 mg, 0.090 mmol), the base of the
title compound was obtained (48 mg, 94%) after purification by
flash chromatography (CH.sub.2Cl.sub.2/MeOH 30:1 to 15:1). The
hydrochloride of the title compound was prepared in accordance with
the general method D.
[0733] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.68 (br s,
1H), 10.41 (s, 1H), 8.87 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.71 (d,
J=8.4 Hz, 2H), 7.57 (s, 1H), 4.84-4.75 (m, 1H), 3.89-3.80 (m, 2H),
3.77-3.68 (m, 2H), 3.47-3.39 (m, 2H), 3.33-3.23 (m, 2H), 3.16-3.08
(m, 2H), 2.73 (s, 3H), 2.68-2.59 (m, 2H), 2.20-2.10 (m, 2H),
1.97-1.90 (m, 2H); MS (ES) m/z 570 (M+1).
Example 35
N-{4-[(Dimethylamino)methyl]phenyl}-5-fluoro-4-[2-methyl-1-(tetrahydro-2H--
pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00083##
[0735]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-
pyrimidin-2-amine (50 mg, 180 .mu.mol, obtained from 7(e)) and
1-(4-bromophenyl)-N,N-dimethylmethanamine (38.6 mg, 180 .mu.mol) in
dry dioxane (2.3 mL) were purged with Ar (gas) for 10 min.
Pd.sub.2(dba).sub.3 (8.3 mg, 9 .mu.mol), X-Phos (8.6 mg, 18
.mu.mol) and Cs.sub.2CO.sub.3 (102 mg, 289 .mu.mol) were added and
Ar (gas) was bubbled through the mixture for 5 min prior to heating
at +90.degree. C. for 47 h. The mixture was allowed to cool,
diluted with CH.sub.2Cl.sub.2 and filtered through diatomaceous
earth. The organics were washed with water, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude was
purified by flash silica gel chromatography CHCl.sub.3/MeOH 9:1-4:1
to give 50 mg (68%).
[0736] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.52 (s, 1H),
8.56 (d, 1H), 7.53 (d, 2H), 7.34 (d, 1H), 7.18 (d, 2H), 5.04 (m,
1H), 3.79 (m, 2H), 3.35 (s, 2H), 3.06 (t, 2H), 2.53 (s, 3H),
2.21-2.11 (m, 8H), 1.78 (m, 2H); MS (ES) m/z 409 (M-1).
Example 36
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(-
1-morpholin-4-ylethyl)phenyl]pyrimidin-2-amine
##STR00084##
[0738]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-
pyrimidin-2-amine (50 mg, 180 .mu.mol, obtained from Example 7(e))
and 4-[1-(4-bromophenyl)ethyl]morpholine (obtained from Example
36(a)) (48.7 mg, 180 .mu.mol) in dry dioxane (2.3 mL) were purged
with Ar (gas) for 10 min. Pd.sub.2(dba).sub.3 (8.3 mg, 9 .mu.mol),
X-Phos (8.6 mg, 18 .mu.mol) and Cs.sub.2CO.sub.3 (102 mg, 289
.mu.mol) were added and Ar (g) was bubbled through the mixture for
5 min prior to heating at +90.degree. C. for 45 h. The mixture was
allowed to cool, diluted with CH.sub.2Cl.sub.2 and filtered through
diatomaceous earth. The organics were washed with water, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude was
purified twice by flash silica gel chromatography CHCl.sub.3/MeOH
20:1 and EtOAc/MeOH 40:1-20:1 to give 53 mg of the title compound
(63%).
[0739] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.51 (s, 1H),
8.55 (d, 1H), 7.52 (d, 2H), 7.33 (d, 1H), 7.18 (d, 2H), 5.05 (m,
1H), 3.80 (m, 2H), 3.54 (t, 4H), 3.28 (q, 1H), 3.08 (t, 2H), 2.53
(s, 3H), 2.37 (m, 2H), 2.28-2.11 (m, 4H), 1.78 (m, 2H), 1.26 (d,
3H); MS (ES) m/z 465 (M-1).
Example 36(a) 4-[1-(4-Bromophenyl)ethyl]morpholine
##STR00085##
[0741] DIPEA (1.98 mL, 11.4 mmol) and morpholine (398 .mu.L, 4.56
mmol) were added to 1-bromo-4-(1-chloroethyl)benzene (Woolman et
al. J. Chem. Soc. 1943, 99-101) (500 mg, 2.28 mmol) in dry MeCN
(2.5 mL) and the solution was heated at +60.degree. C. for 72 h.
The mixture was allowed to cool, concentrated and diluted in
CH.sub.2Cl.sub.2. The organics were washed by water, brine and
water, dried (Na.sub.2SO.sub.4), filtered and concentrated to give
616 mg (100%) of the desired product.
[0742] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.50 (m, 2H),
7.26 (m, 2H), 3.54 (m, 4H), 3.33 (q, 1H), 2.38 (m, 2H), 2.24 (m,
2H), 1.24 (d, 3H); MS (ES) m/z 270/272 (M/M+2).
Example 37
N-[4-(1-Azetidin-1-ylethyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-p-
yran-4-yl)-1H-4-imidazol-5-yl]pyrimidin-2-amine
##STR00086##
[0744]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-
pyrimidin-2-amine (50 mg, 180 .mu.mol, obtained from Example 7(e))
and 1-[1-(4-bromophenyl)ethyl]azetidine (obtained from Example
37(a)) (43.3 mg, 180 .mu.mol) in dry dioxane (2.3 mL) were purged
with Ar (gas) for 10 min. Pd.sub.2(dba).sub.3 (8.3 mg, 9 .mu.mol),
X-Phos (8.6 mg, 18 .mu.mol) and Cs.sub.2CO.sub.3 (102 mg, 289
.mu.mol) were added and Ar (g) was bubbled through the mixture for
5 min prior to heating at +90.degree. C. for 51 h. The mixture was
allowed to cool, diluted with CH.sub.2Cl.sub.2 and filtered through
diatomaceous earth. The organics were washed with water, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude was
purified by flash silica gel chromatography CHCl.sub.3/MeOH 9:1-3:1
to give 40 mg (51%).
[0745] .sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 8.39 (d, 1H), 7.55
(d, 2H), 7.42 (d, 1H), 7.26 (d, 2H), 5.21 (m, 1H), 3.91 (m 2H),
3.52 (m, 1H), 3.41 (m, 2H), 3.25 (m, 2H), 3.19 (t, 2H), 2.61 (s,
3H), 2.34 (m, 2H), 2.11 (quintet, 2H), 1.86 (m, 2H), 1.27 (d, 3H);
MS (ES) m/z 435 (M-1).
Example 37(a) 1-[1-(4-Bromophenyl)ethyl]azetidine
##STR00087##
[0747] DIPEA (1.98 mL, 11.4 mmol) and azetidine (307 .mu.L, 4.56
mmol) were added to 1-bromo-4-(1-chloroethyl)benzene (Woolman et
al. J. Chem. Soc. 1943, 99-101) (500 mg, 2.28 mmol) in dry MeCN
(2.5 mL) and the solution was heated at +60.degree. C. for 74 h.
More azetidine (100 .mu.L, 1.48 mmol) was added, and after heating
for 23 more hours. even more azetidine (100 .mu.L, 1.48 mmol) and
DIPEA (500 .mu.L, 2.87 mmol) were added and the mixture was heated
for a further 27 h. After cooling and concentration the crude was
diluted with CH.sub.2Cl.sub.2. The organics were washed with water,
brine and water, dried Na.sub.2SO.sub.4), filtered and concentrated
to give 481 mg (87%) of the desired product.
[0748] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.47 (m, 2H),
7.24 (m, 2H), 3.22 (q, 1H), 3.04 (m, 2H), 2.96 (m, 2H), 1.88
(quintet, 2H), 1.05 (d, 3H); MS (ES) m/z 240/242 (M/M+2).
Example 38
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(-
2-morpholin-4-ylethyl)phenyl]pyrimidin-2-amine
##STR00088##
[0750]
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-
pyrimidin-2-amine (50 mg, 180 .mu.mol, obtained from Example 7(e))
and 4-[2-(4-bromophenyl)ethyl]morpholine (King et al. Tet. Lett.
2005, 46, 1471-1474) (48.7 mg, 180 .mu.mol) in dry dioxane (2.3 mL)
were purged with Ar (gas) for 10 min. Pd.sub.2(dba).sub.3 (8.3 mg,
9 .mu.mol), X-Phos (8.6 mg, 18 .mu.mol) and Cs.sub.2CO.sub.3 (102
mg, 289 .mu.mol) were added and Ar (g) was bubbled through the
mixture for 5 min prior to heating at +90.degree. C. for 72 h. The
mixture was allowed to cool, diluted with CH.sub.2Cl.sub.2 and
filtered through diatomaceous earth. The organics were washed with
water, dried (Na.sub.2SO.sub.4), filtered and concentrated. The
crude was purified by flash silica gel chromatography EtOAc/MeOH
20:1-5:1, the residue was dissolved in CHCl.sub.3 and filtered
through tightly packed glass wool and concentrated to give 41 mg of
the title compound (49%).
[0751] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.42 (s, 1H),
8.53 (d, 1H), 7.46 (d, 2H), 7.33 (d, 1H), 7.12 (d, 2H), 5.03 (m,
1H), 3.80 (m, 2H), 3.57 (t, 4H), 3.03 (t, 2H), 2.68 (t, 2H), 2.53
(s, 3H), 2.47 (m, 2H), 2.41 (m, 4H), 2.15 (m, 2H), 1.76 (m, 2H); MS
(ES) m/z 467 (M+1).
Example 39
N-[4-(Methylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-i-
midazol-5-yl]pyrimidin-2-amine
##STR00089##
[0753] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (obtained from Example 39(a)) (60.4 mg, 0.233 mmol),
1-bromo-4-(methylsulfonyl)benzene (54.8 mg, 0.233 mmol),
Cs.sub.2CO.sub.3 (152 mg, 0.466 mmol), Pd.sub.2(dba).sub.3 (5 mg,
0.006 mmol) and X-Phos (7 mg, 0.012 mmol) to give the title
compound (48 mg, 50%).
[0754] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.43 (d, J=5.3
Hz, 1H) 7.96 (s, 1H) 7.78-7.88 (m, 4H) 7.43 (s, 1H) 7.02 (d, J=5.3
Hz, 1H) 5.12-5.24 (m, 1H) 4.04 (dd, J=1.5, 4.4 Hz, 2H) 3.24-3.34
(m, 2H) 3.04 (s, 3H) 2.61 (s, 3H) 2.39-2.53 (m, 2H) 1.85 (dd,
J=12.4, 2.8 Hz, 2H); MS (ESI) m/z 414 (M+1).
Example 39(a)
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne
##STR00090##
[0756]
(2E)-3-Dimethylamino-1-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-im-
idazol-5-yl]prop-2-en-1-one (described within WO 2005101997) (1.824
g, 6.925 mmol) and guanidine carbonate (3.12 g, 17.31 mmol) were
dissolved in n-BuOH (31 mL) and MeONa (1.50 g, 27.70 mmol) was
added. The mixture was heated at +125.degree. C. (oil bath
temperature) for 20 hours. Saturated NH.sub.4Cl (20 mL) was added
and the mixture was extracted with CH.sub.2Cl.sub.2 (3.times.30
mL). Drying (Na.sub.2SO.sub.4), filtration and concentration gave a
crude product which was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH 25:1.fwdarw.20:1.fwdarw.15:1) to afford a
solid (1.3 g, 72%).
[0757] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.24 (d, J=5.3
Hz, 1H) 7.37 (s, 1H) 6.83 (d, J=5.3 Hz, 1H) 5.23-5.34 (m, 1H) 5.04
(s, 2H) 4.13 (dd, J=11.6, 4.5 Hz, 2H) 3.44-3.54 (m, 2H) 2.60 (s,
3H) 2.43-2.56 (m, 2H) 1.85-1.93 (m, 2H); MS (ESI) m/z 260
(M+1).
Example 40
N-{4-[(4-Methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2-
H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00091##
[0759] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (64.6 mg, 0.249 mmol, obtained Example 39(a)),
1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (described in WO
2003004472) (79.5 mg, 0.249 mmol), Cs.sub.2CO.sub.3 (162 mg, 0.498
mmol), Pd.sub.2(dba).sub.3 (6 mg, 0.006 mmol) and X-Phos (7 mg,
0.013 mmol) to give the title compound (54 mg, 43%).
[0760] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.42 (d, J=5.3
Hz, 1H) 7.89 (s, 1H) 7.75-7.81 (m, 2H) 7.65 (d, J=8.8 Hz, 2H) 7.41
(s, 1H) 7.00 (d, J=5.3 Hz, 1H) 5.12-5.26 (m, 1H) 4.05 (dd, J=1.6,
4.3 Hz, 2H) 3.24-3.36 (m, 2H) 3.02 (s, 4H) 2.61 (s, 3H) 2.37-2.53
(m, 6H) 2.24 (s, 3H) 1.85 (dd, J=12.1, 2.8 Hz, 2H); MS (ESI) m/z
498 (M+1).
Example 41
N-{4-[(4-Methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2-
H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00092##
[0762] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (64.5 mg, 0.249 mmol, obtained Example 39(a)),
1-(4-bromobenzoyl)-4-methylpiperazine (described in WO 2003004472)
(70.4 mg, 0.249 mmol), Cs.sub.2CO.sub.3 (162 mg, 0.497 mmol),
Pd.sub.2(dba).sub.3 (6 mg, 0.006 mmol) and X-Phos (7 mg, 0.012
mmol) to give the title compound (42 mg, 37%).
[0763] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.38 (d, J=5.3
Hz, 1H) 7.69 (s, 1H) 7.62 (d, J=8.6 Hz, 2H) 7.33-7.42 (m, 3H) 6.94
(d, J=5.3 Hz, 1H) 5.17-5.27 (m, 1H) 4.01 (dd, J=11.5, 4.4 Hz, 2H)
3.64 (s, 4H) 3.16-3.32 (m, 2H) 2.60 (s, 3H) 2.33-2.53 (m, 6H) 2.31
(s, 3H) 1.84 (dd, J=12.3, 2.7 Hz, 2H); MS (ESI) m/z 462 (M+1).
Example 42
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholin-
-4-ylmethyl)phenyl]pyrimidin-2-amine
##STR00093##
[0765] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (65.8 mg, 0.254 mmol, obtained Example 39(a)),
4-(4-bromobenzyl)morpholine (65.0 mg, 0.254 mmol), Cs.sub.2CO.sub.3
(165 mg, 0.508 mmol), Pd.sub.2(dba).sub.3 (6 mg, 0.006 mmol) and
X-Phos (7 mg, 0.013 mmol) to give the title compound (24 mg,
21%).
[0766] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.29 (d, J=5.3
Hz, 1H) 7.42 (d, J=8.3 Hz, 2H) 7.31 (s, 2H) 7.19 (d, J=7.8 Hz, 2H)
6.83 (d, J=5.3 Hz, 1H) 5.16-5.28 (m, 1H) 3.88 (dd, J=1.6, 4.3 Hz,
2H) 3.59-3.68 (m, 4H) 3.39 (s, 2H) 3.03-3.14 (m, 2H) 2.54 (s, 3H)
2.35-2.42 (m, 4H) 2.22-2.35 (m, 2H) 1.76 (dd, J=12.3, 2.4 Hz, 2H);
MS (ESI) m/z 435 (M+1).
Example 43
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(morpholin-
-4-ylsulfonyl)phenyl]pyrimidin-2-amine
##STR00094##
[0768] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (66.5 mg, 0.256 mmol, obtained Example 39(a)),
4-[(4-bromophenyl)sulfonyl]morpholine (78.5 mg, 0.256 mmol),
Cs.sub.2CO.sub.3 (167 mg, 0.513 mmol), Pd.sub.2(dba).sub.3 (6 mg,
0.006 mmol) and X-Phos (7 mg, 0.013 mmol) to give the title
compound (30 mg, 24%).
[0769] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.44 (d, J=5.3
Hz, 1H) 7.83 (d, J=8.8 Hz, 2H) 7.69 (d, J=8.8 Hz, 2H) 7.64 (s, 1H)
7.45 (s, 1H) 7.03 (d, J=5.3 Hz, 1H) 5.10-5.24 (m, 1H) 4.09 (dd,
J=11.5, 4.4 Hz, 2H) 3.69-3.80 (m, 4H) 3.30-3.41 (m, 2H) 2.94-3.07
(m, 4H) 2.63 (s, 3H) 2.44-2.59 (m, 2H) 1.87 (dd, J=12.4, 2.8 Hz,
2H); MS (ESI) m/z 485 (+1).
Example 44
N-(4-{[4-(2-Methoxyethyl)piperazin-1-yl]sulfonyl}phenyl)-4-[2-methyl-1-(te-
trahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00095##
[0771] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (76.0 mg, 0.293 mmol, obtained from Example 39(a)),
1-[(4-bromophenyl)sulfonyl]-4-(2-methoxyethyl)piperazine (106.5 mg,
0.293 mmol, obtained from Example 44(a)), Cs.sub.2CO.sub.3 (191 mg,
0.586 mmol), Pd.sub.2(dba).sub.3 (7 mg, 0.007 mmol) and X-Phos (9
mg, 0.015 mmol) to give the title compound (41 mg, 26%).
[0772] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.43 (d, J=5.3
Hz, 1H) 7.78 (d, J=9.1 Hz, 3H) 7.66 (d, J=8.8 Hz, 2H) 7.42 (s, 1H)
7.01 (d, J=5.3 Hz, 1H) 5.14-5.25 (m, 1H) 4.06 (dd, J=11.5, 4.4 Hz,
2H) 3.43 (t, J=5.3 Hz, 2H) 3.26-3.37 (m, 5H) 3.05 (s, 4H) 2.62 (s,
3H) 2.55 (q, J=5.5 Hz, 6H) 2.40-2.53 (m, 2H) 1.86 (dd, J=12.3, 2.7
Hz, 2H); MS (ESI) m/z 542 (M+1).
Example 44(a)
1-[(4-Bromophenyl)sulfonyl]-4-(2-methoxyethyl)piperazine
##STR00096##
[0774] The title compound was prepared in accordance with the
general method F using 4-bromobenzenesulfonyl chloride (201.7 mg,
0.789 mmol) and 1-(2-methoxyethyl)piperazine (113.8 mg, 0.789 mmol)
to give the title compound (277 mg, 97%).
[0775] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.64-7.69 (m,
2H) 7.57-7.62 (m, 2H) 3.47 (t, J=5.2 Hz, 2H) 3.30 (s, 3H) 3.08 (s,
4H) 2.62 (d, J=4.8 Hz, 6H); MS (ESI) m/z 364 (M+1).
Example 45
N-{4-[(4-Isopropylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydr-
o-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00097##
[0777] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (72.4 mg, 0.279 mmol, obtained from Example 39(a)),
1-[(4-bromophenyl)sulfonyl]-4-isopropylpiperazine (prepared as
described in Example 45a) (97.0 mg, 0.279 mmol), Cs.sub.2CO.sub.3
(182.0 mg, 0.559 mmol), Pd.sub.2(dba).sub.3 (6 mg, 0.007 mmol) and
X-Phos (8 mg, 0.014 mmol) to give the title compound (35 mg,
24%).
[0778] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.43 (d, J=5.1
Hz, 1H) 7.75-7.81 (m, 2H) 7.72 (s, 1H) 7.67 (d, J=8.6 Hz, 2H) 7.43
(s, 1H) 7.02 (d, J=5.1 Hz, 1H) 5.14-5.25 (m, 1H) 4.07 (dd, J=1.5,
4.4 Hz, 2H) 3.27-3.38 (m, 2H) 3.02 (s, 4H) 2.64-2.71 (m, 1H) 2.62
(s, 3H) 2.55-2.61 (m, 4H) 2.41-2.54 (m, 2H) 1.86 (dd, J=12.4, 2.8
Hz, 2H) 0.99 (d, J=6.6 Hz, 6H); MS (ESI) m/z 526 (M+1).
Example 45(a) 1-[(4-Bromophenyl)sulfonyl]-4-isopropylpiperazine
##STR00098##
[0780] The title compound was prepared in accordance with the
general method F using 4-bromobenzenesulfonyl chloride (272.5 mg,
1.067 mmol) and 1-isopropylpiperazine (136.7 mg, 1.067 mmol) to
give the title compound (360 mg, 97%).
[0781] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.64-7.70 (m,
2H) 7.59-7.64 (m, 2H) 3.02 (s, 4H) 2.64-2.72 (m, 1H) 2.55-2.63 (m,
4H) 1.00 (d, J=6.6 Hz, 6H); MS (ESI) m/z 348 (M+1).
Example 46
4-[2-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-N-[4-(pyrrolidi-
n-1-ylsulfonyl)phenyl]pyrimidin-2-amine
##STR00099##
[0783] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (62.4 mg, 0.241 mmol, obtained from Example 39(a)),
1-[(4-bromophenyl)sulfonyl]pyrrolidine (69.8 mg, 0.241 mmol),
Cs.sub.2CO.sub.3 (156.8 mg, 0.481 mmol), Pd.sub.2(dba).sub.3 (6 mg,
0.006 mmol) and X-Phos (7 mg, 0.012 mmol) to give the title
compound (58 mg, 51%).
[0784] .sup.1H NMR (400 MHz, CDCl.sub.3) 5 ppm 8.43 (d, J=5.3 Hz,
1H) 7.86 (s, 1H) 7.72-7.81 (m, 4H) 7.42 (s, 1H) 7.00 (d, J=5.3 Hz,
1H) 5.13-5.24 (m, 1H) 4.05 (dd, J=11.5, 4.4 Hz, 2H) 3.26-3.36 (m,
2H) 3.18-3.26 (m, 4H) 2.61 (s, 3H) 2.40-2.53 (m, 2H) 1.85 (dd,
J=12.3, 2.7 Hz, 2H) 1.70-1.78 (m, 4H); MS (ESI) m/z 469 (M+1).
Example 47
(N-(1-Methylpiperidin-4-yl)-4-({4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1-
H-imidazol-5-yl]pyrimidin-2-yl}amino)benzenesulfonamide
##STR00100##
[0786] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl-1H-imidazol-5-yl]pyrimidin-2-amin-
e (71.5 mg, 0.276 mmol, obtained from Example 39(a)),
4-bromo-N-(1-methylpiperidin-4-yl)benzenesulfonamide (obtained from
Example 47(a)) (91.9 mg, 0.276 mmol), Cs.sub.2CO.sub.3 (179.7 mg,
0.552 mmol), Pd.sub.2(dba).sub.3 (6 mg, 0.007 mmol) and X-Phos (8
mg, 0.014 mmol) to give the title compound (61 mg, 43%).
[0787] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.44 (d, J=5.3
Hz, 1H) 7.81 (q, J=9.1 Hz, 4H) 7.45 (s, 1H) 7.04 (d, J==5.3 Hz, 1H)
5.12-5.24 (m, 1H) 4.10 (dd, J=11.6, 4.5 Hz, 2H) 3.34 (t, J=1.1 Hz,
2H) 3.00 (s, 2H) 2.62-2.68 (m, 4H) 2.53 (dd, J=12.6, 4.5 Hz, 4H)
2.45 (s, 3H) 2.02 (s, 3H) 1.88 (dd, J=12.9, 3.3 Hz, 2H) some
overlap of protons; MS (ESI) m/z 512 (M+1).
Example 47(a)
4-Bromo-N-(1-methylpiperidin-4-yl)benzenesulfonamide
##STR00101##
[0789] The title compound was prepared in accordance with the
general method F using 4-bromobenzenesulfonyl chloride (200.5 mg,
0.785 mmol) and 1-methylpiperidin-4-amine (89.6 mg, 0.785 mmol) to
give the title compound (245 mg, 94%).
[0790] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.72-7.78 (m,
2H) 7.63-7.68 (m, 2H) 3.11-3.22 (m, 1H) 2.70 (d, J=11.6 Hz, 2H)
2.24 (s, 3H) 2.03 (t, J=10.9 Hz, 2H) 1.73-1.83 (m, 2H) 1.44-1.57
(m, 2H); MS (ESI) m/z 334 (M+1).
Example 48
N-{4-[(4-Methyl-1,4-diazepan-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahyd-
ro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00102##
[0792] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (53.0 mg, 0.204 mmol, obtained from Example 39(a)),
1-[(4-bromophenyl)sulfonyl]-4-methyl-1,4-diazepane (as described in
WO 2003004472) (75.6 mg, 0.204 mmol), Cs.sub.2CO.sub.3 (199.8 mg,
0.613 mmol), Pd.sub.2(dba).sub.3 (5 mg, 0.005 mmol) and X-Phos (6
mg, 0.010 mmol) to give the title compound (15 mg, 15%).
[0793] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.43 (d, J=5.3
Hz, 1H) 7.69-7.81 (m, 4H) 7.61 (s, 1H) 7.44 (s, 1H) 7.02 (d, J=5.3
Hz, 1H) 5.12-5.24 (m, 1H) 4.08 (dd, J=11.6, 4.5 Hz, 2H) 3.27-3.46
(m, 6H) 2.64-2.73 (m, 4H) 2.63 (s, 3H) 2.44-2.57 (m, 2H) 2.38 (s,
3H) 1.82-1.94 (m, 4H); MS (ESI) m/z 512 (M+1).
Example 49
N,N-Diethyl-4-({4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]-
pyrimidin-2-yl}amino)benzenesulfonamide
##STR00103##
[0795] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (54.9 mg, 0.212 mmol, obtained from Example 39(a)),
4-bromo-N,N-diethylbenzenesulfonamide (as described in J. Med.
Chem., 2000, 43, 3878) (61.9 mg, 0.212 mmol), Cs.sub.2CO.sub.3
(138.0 mg, 0.423 mmol), Pd.sub.2(dba).sub.3 (5 mg, 0.005 mmol) and
X-Phos (6 mg, 0.011 mmol) to give the title compound (69 mg,
69%).
[0796] .sup.1H NMR (400 MHz, CDCl.sub.3) 5 ppm 8.41 (d, J=5.3 Hz,
1H) 7.96 (s, 1H) 7.67-7.77 (m, 4H) 7.40 (s, 1H) 6.99 (d, J=5.1 Hz,
1H) 5.13-5.24 (m, 1H) 4.02 (dd, J=11.5, 4.4 Hz, 2H) 3.24-3.33 (m,
2H) 3.21 (q, J=7.2 Hz, 4H) 2.60 (s, 3H) 2.36-2.51 (m, 2H) 1.84 (dd,
J=12.4, 2.8 Hz, 2H) 1.11 (t, J=7.2 Hz, 6H); MS (ESI) m/z 471
(M+1).
Example 50
N-[4-(Azetidin-1-ylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyran-4-y-
l)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00104##
[0798] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (59.2 mg, 0.228 mmol, obtained from Example 39(a)),
1-[(4-bromophenyl)sulfonyl]azetidine (obtained from Example 50(a))
(63.0 mg, 0.228 mmol), Cs.sub.2CO.sub.3 (148.8 mg, 0.457 mmol),
Pd.sub.2(dba).sub.3 (5 mg, 0.006 mmol) and X-Phos (7 mg, 0.011
mmol) to give the title compound (28 mg, 27%).
[0799] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.45 (d, J=5.3
Hz, 1H) 7.81-7.88 (m, 2H) 7.74-7.81 (m, 3H) 7.44 (s, 1H) 7.03 (d,
J=5.3 Hz, 1H) 5.13-5.25 (m, 1H) 4.08 (dd, J=11.6, 4.5 Hz, 2H) 3.77
(t, J=7.7 Hz, 4H) 3.28-3.39 (m, 2H) 2.63 (s, 3H) 2.43-2.57 (m, 2H)
2.02-2.11 (m, 2H) 1.87 (dd, J=12.4, 2.8 Hz, 2H); MS (ESI) m/z 455
(+1).
Example 50(a) 1-[(4-Bromophenyl)sulfonyl]azetidine
##STR00105##
[0801] The title compound was prepared in accordance with the
general method F using 4-bromobenzenesulfonyl chloride (314.4 mg,
1.230 mmol) and azetidine (70.3 mg, 1.230 mmol) to give the title
compound (315 mg, 93%).
[0802] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.72 (d, J=1.5
Hz, 4H) 3.80 (t, 4H) 2.06-2.17 (m, 2H); MS (ESI) m/z 277 (M+1).
Example 51
N-{3-[(4-Methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro-2-
H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00106##
[0804] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (60.1 mg, 0.232 mmol, obtained from Example 39(a)),
1-[(3-bromophenyl)sulfonyl]-4-methylpiperazine (obtained from
Example 51a) (74.0 mg, 0.232 mmol), Cs.sub.2CO.sub.3 (151.0 mg,
0.464 mmol), Pd.sub.2(dba).sub.3 (5 mg, 0.006 mmol) and X-Phos (7
mg, 0.012 mmol) to give the title compound (65 mg, 57%).
[0805] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.38 (d, J=5.3
Hz, 1H) 8.00 (s, 1H) 7.96 (s, 1H) 7.86 (d, J=8.6 Hz, 1H) 7.34-7.46
(m, 3H) 6.95 (d, J=5.3 Hz, 1H) 5.12-5.24 (m, 1H) 3.99 (dd, J=11.5,
4.2 Hz, 2H) 3.20 (t, J=11.2 Hz, 2H) 3.03 (s, 4H) 2.59 (s, 3H)
2.30-2.48 (m, 6H) 2.22 (s, 3H) 1.84 (dd, J=12.1, 2.5 Hz, 2H); MS
(ESI) m/z 498 (M+1).
Example 51 (a) 1-[(3-Bromophenyl)sulfonyl]-4-methylpiperazine
##STR00107##
[0807] The title compound was prepared in accordance with the
general method F using 3-bromobenzenesulfonyl chloride (357.1 mg,
1.398 mmol) and 1-methylpiperazine (153.9 mg, 1.537 mmol) to give
the title compound (393 mg, 100%).
[0808] .sup.1H NMR (400 MHz, CDCl.sub.3) 5 ppm 7.90 (t, J=1.8 Hz,
1H) 7.71-7.75 (m, 1H) 7.66-7.70 (m, 1H) 7.41 (t, J=8.0 Hz, 1H) 3.06
(s, 4H) 2.45-2.53 (m, 4H) 2.28 (s, 3H); MS (ESI) m/z 320 (M+1).
Example 52
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00108##
[0810] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (59.0 mg, 0.228 mmol, obtained from Example 39(a)),
1-[(4-bromo-2-chlorophenyl)sulfonyl]-4-methylpiperazine (obtained
from Example 52(a)) (80.5 mg, 0.228 mmol), Cs.sub.2CO.sub.3 (148.3
mg, 0.455 mmol), Pd.sub.2(dba).sub.3 (5 mg, 0.006 mmol) and X-Phos
(7 mg, 0.011 mmol) to give the title compound (59 mg, 49%).
[0811] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.43 (d, J=5.3
Hz, 1H) 8.05 (s, 1H) 8.00 (d, J=2.3 Hz, 1H) 7.90 (d, J=8.8 Hz, 1H)
7.50 (dd, J=8.7, 2.1 Hz, 1H) 7.42 (s, 1H) 7.03 (d, J=5.3 Hz, 1H)
5.12-5.24 (m, 1H) 4.05 (dd, J=11.5, 4.4 Hz, 2H) 3.22-3.35 (m, 6H)
2.61 (s, 3H) 2.37-2.52 (m, 6H) 2.26 (s, 3H) 1.87 (dd, J=12.4, 2.8
Hz, 2H); MS (ESI) m/z 533 (M+1).
Example 52(a)
1-[(4-Bromo-2-chlorophenyl)sulfonyl]-4-methylpiperazine
##STR00109##
[0813] The title compound was prepared in accordance with the
general method F using 4-bromo-2-chlorobenzenesulfonyl chloride
(326.0 mg, 1.124 mmol) and 1-methylpiperazine (123.9 mg, 1.234
mmol) to give the title compound (406 mg, 100%).
[0814] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.86 (d, J=8.6
Hz, 1H) 7.67 (d, J=1.8 Hz, 1H) 7.51 (dd, J=8.6, 2.0 Hz, 1H)
3.26-3.34 (m, 4H) 2.42-2.49 (m, 4H) 2.29 (s, 3H); MS (ESI) m/z 354
(M+1).
Example 53
N-{3-Methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00110##
[0816] The title compound was prepared in accordance with the
general method E using
4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (60.1 mg, 0.232 mmol, obtained from Example 39(a)),
1-[(4-bromo-2-methylphenyl)sulfonyl]-4-methylpiperazine (obtained
from Example 53(a)) (77.2 mg, 0.232 mmol), Cs.sub.2CO.sub.3 (151.0
mg, 0.463 mmol), Pd.sub.2(dba).sub.3 (5 mg, 0.006 mmol) and X-Phos
(7 mg, 0.012 mmol) to give the title compound (49 mg, 41%).
[0817] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.42 (d, J=5.3
Hz, 1H) 7.81 (d, J=8.6 Hz, 1H) 7.63-7.70 (m, 2H) 7.46 (d, J=2.0 Hz,
1H) 7.42 (s, 1H) 6.99 (d, J=5.3 Hz, 1H) 5.13-5.25 (m, 1H) 4.05 (dd,
J=11.6, 4.3 Hz, 2H) 3.24-3.35 (m, 2H) 3.11-3.22 (m, 4H) 2.60 (d,
J=7.6 Hz, 6H) 2.38-2.53 (m, 6H) 2.27 (s, 3H) 1.84 (dd, J=12.3, 2.7
Hz, 2H); MS (ESI) m/z 512 (M+1).
Example 53(a)
1-[(4-Bromo-2-methylphenyl)sulfonyl]-4-methylpiperazine
##STR00111##
[0819] The title compound was prepared in accordance with the
general method F using 4-bromo-2-methylbenzenesulfonyl chloride
(332.6 mg, 1.234 mmol) and 1-methylpiperazine (135.9 mg, 1.357
mmol) to give the title compound (411 mg, 100%).
[0820] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.75 (d, J=8.3
Hz, 1H) 7.44-7.52 (m, 2H) 3.23 (s, 4H) 2.61 (s, 3H) 2.49 (s, 4H)
2.32 (s, 3H); MS (ESI) m/z 334 (M+1).
Example 54
5-Fluoro-N-(4-{[(3R)-3-methylmorpholin-4-yl]sulfonyl}phenyl)-4-[2-methyl-1-
-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00112##
[0822] The title compound was prepared in accordance with the
general method E using
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (52.0 mg, 0.188 mmol, obtained from Example 7(e)),
(3R)-4-[(4-bromophenyl)sulfonyl]-3-methylmorpholine (obtained from
Example 54(a)) (60.0 mg, 0.188 mmol), Cs.sub.2CO.sub.3 (122.2 mg,
0.375 mmol), Pd.sub.2(dba).sub.3 (4 mg, 0.005 mmol) and X-Phos (7
mg, 0.009 mmol) to give the title compound (24 mg, 25%).
[0823] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.36 (d, J=3.0
Hz, 1H) 7.70-7.77 (m, 5H) 7.68 (d, J=3.8 Hz, 1H) 4.99-5.12 (m, 1H)
4.10 (dd, J=11.7, 4.7 Hz, 2H) 3.92 (q, J=6.7 Hz, 1H) 3.78-3.85 (m,
1H) 3.54-3.63 (m, 2H) 3.40-3.52 (m, 2H) 3.34 (t, J=11.6 Hz, 2H)
3.21-3.30 (m, 1H) 2.65 (s, 3H) 2.48-2.62 (m, 2H) 1.87 (dd, J=12.8,
3.7 Hz, 2H) 1.17 (d, J=6.8 Hz, 3H); MS (ESI) m/z 517 (M+1).
Example 54(a)
(3R)-4-[(4-Bromophenyl)sulfonyl]-3-methylmorpholine
##STR00113##
[0825] The title compound was prepared in accordance with the
general method F using 4-bromobenzenesulfonyl chloride (294.9 mg,
1.154 mmol) and (3R)-3-methylmorpholine (128.4 mg, 1.269 mmol) to
give the title compound (368 mg, 99%).
[0826] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.67 (d, J=2.3
Hz, 4H) 3.80-3.86 (m, 1H) 3.58 (d, J=2.3 Hz, 2H) 3.42-3.50 (m, 2H)
3.21-3.30 (m, 1H) 1.45 (d, J=6.6 Hz, 1H) 1.15 (d, J=6.8 Hz, 3H); MS
(ESI) m/z 321 (M+1).
Example 55
5-Fluoro-N-{3-methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-[2-meth-
yl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00114##
[0828] The title compound was prepared in accordance with the
general method E using
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (54.6 mg, 0.202 mmol, obtained from Example 7(e)),
1-[(4-bromo-2-methylphenyl)sulfonyl]-4-methylpiperazine (obtained
from Example 53(a)) (67.3 mg, 0.202 mmol), Cs.sub.2CO.sub.3 (131.6
mg, 0.404 mmol), Pd.sub.2(dba).sub.3 (5 mg, 0.005 mmol) and X-Phos
(6 mg, 0.010 mmol) to give the title compound (46 mg, 43%).
[0829] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.34 (d, J=2.8
Hz, 1H) 7.81 (d, J=8.6 Hz, 1H) 7.65 (d, J=3.8 Hz, 1H) 7.57-7.63 (m,
2H) 7.42 (d, J=2.0 Hz, 1H) 5.03-5.14 (m, 1H) 4.07 (dd, J=11.6, 4.5
Hz, 2H) 3.26-3.37 (m, 2H) 3.11-3.23 (m, 4H) 2.63 (s, 3H) 2.59 (s, 3
H) 2.39-2.57 (m, 6H) 2.27 (s, 3H) 1.85 (dd, J=12.1, 3.0 Hz, 2H); MS
(ESI) m/z 530 (M+1).
Example 56
5-Fluoro-N-(4-{[(1S,4S)-2,5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfon-
yl}phenyl)-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrim-
idin-2-amine
##STR00115##
[0831] The title compound was prepared in accordance with the
general method E using
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (53.3 mg, 0.197 mmol, obtained from Example 7(e)),
(1S,4S)-2-[(4-bromophenyl)sulfonyl]-5-methyl-2,5-diazabicyclo[2.2.1]hepta-
ne (obtained from Example 56(a)) (65.3 mg, 0.197 mmol),
Cs.sub.2CO.sub.3 (128.5 mg, 0.394 mmol), Pd.sub.2(dba).sub.3 (5 mg,
0.005 mmol) and X-Phos (6 mg, 0.010 mmol) to give the title
compound (60 mg, 57%).
[0832] .sup.1H NMR (400 MHz, CDCl.sub.3) 5 ppm 8.34 (d, J=2.8 Hz,
1H) 7.88 (s, 1H) 7.73 (s, 4H) 7.64 (d, J=3.8 Hz, 1H) 5.00-5.12 (m,
1H) 4.22 (s, 1H) 4.06 (dd, J=11.6, 4.5 Hz, 2H) 3.53 (d, J=9.9 Hz,
1H) 3.27-3.37 (m, 3H) 3.00 (dd, J=9.6, 2.3 Hz, 1H) 2.83 (dd, J=9.9,
2.5 Hz, 1H) 2.65 (s, 1H) 2.62 (s, 3H) 2.43-2.57 (m, 2H) 2.33 (s,
3H) 1.85 (dd, J=12.5, 3.4 Hz, 2H) 1.67 (d, J=9.9 Hz, 1H) 1.12 (d,
J=10.1 Hz, 1H); MS (ESI) m/z 528 (M+1).
Example 56(a)
(1S,4S)-2-[(4-Bromophenyl)sulfonyl]-5-methyl-2,5-diazabicyclo[2.2.1]hepta-
ne
##STR00116##
[0834] The title compound was prepared in accordance with the
general method F using 4-bromobenzenesulfonyl chloride (309.0 mg,
1.209 mmol), (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane
hydrobromide (364.5 mg, 1.330 mmol) and also adding Et.sub.3N
(367.1 mg, 3.628 mmol) to give the title compound (400 mg,
100%).
[0835] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.65-7.73 (m,
4H) 4.27 (s, 1H) 3.56 (dd, J=9.6, 1.3 Hz, 1H) 3.36 (s, 1H) 3.02
(dd, J=9.6, 2.3 Hz, 1H) 2.86 (dd, J=9.9, 2.5 Hz, 1H) 2.65 (dd,
J=10.0, 1.1 Hz, 1H) 2.36 (s, 3H) 1.74 (d, J=9.9 Hz, 1H) 1.17 (d,
J=9.9 Hz, 1H); MS (ESI) m/z 332 (M+1).
Example 57
4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyr-
imidin-2-yl}amino)-N,N-dimethylbenzenesulfonamide
##STR00117##
[0837] The title compound was prepared in accordance with the
general method E using
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (54.1 mg, 0.200 mmol, obtained from Example 7(e)),
4-bromo-N,N-dimethylbenzenesulfonamide (52.9 mg, 0.200 mmol),
Cs.sub.2CO.sub.3 (130.4 mg, 0.400 mmol), Pd.sub.2(dba).sub.3 (5 mg,
0.005 mmol) and X-Phos (6 mg, 0.010 mmol) to give the title
compound (44 mg, 47%).
[0838] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.35 (d, J=2.8
Hz, 1H) 7.82 (s, 1H) 7.73-7.78 (m, 2H) 7.67-7.71 (m, 2H) 7.65 (d,
J=3.8 Hz, 1H) 5.03-5.13 (m, 1H) 4.07 (dd, J=11.6, 4.5 Hz, 2H)
3.28-3.38 (m, 2H) 2.69 (s, 6H) 2.64 (s, 3H) 2.44-2.58 (m, 2H) 1.86
(dd, J=12.1, 3.0 Hz, 2H); MS (ESI) m/z 461 (M+1).
Example 58
N-[4-(Azetidin-1-ylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H--
pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00118##
[0840] The title compound was prepared in accordance with the
general method E using
5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (54.3 mg, 0.201 mmol, obtained from Example 7(e)),
1-[(4-bromophenyl)sulfonyl]azetidine (55.5 mg, 0.201 mmol, obtained
from Example 50(a)), Cs.sub.2CO.sub.3 (130.9 mg, 0.402 mmol),
Pd.sub.2(dba).sub.3 (5 mg, 0.005 mmol) and X-Phos (6 mg, 0.010
mmol) to give the title compound (38 mg, 40%).
[0841] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.36 (d, J=3.0
Hz, 1H) 7.85 (s, 1H) 7.73-7.83 (m, 4H) 7.66 (d, J=3.8 Hz, 1H)
5.00-5.17 (m, 1H) 4.08 (dd, J=1.6, 4.8 Hz, 2H) 3.76 (t, J=7.7 Hz,
4H) 3.28-3.40 (m, 2H) 2.64 (s, 3H) 2.44-2.59 (m, 2H) 2.01-2.13 (m,
2H) 1.87 (dd, J=12.3, 3.2 Hz, 2H); MS (ESI) m/z 473 (M+1).
Example 59
Methyl
3-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}-
benzoate
##STR00119##
[0843]
2-Chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidine (49
mg, 0.22 mmol, 1.0 equiv., obtained from Example 1(b)),
methyl-3-aminobenzoate (38 mg, 0.25 mmol, 1.15 equiv.) and
Cs.sub.2CO.sub.3 (0.11 g, 0.33 mmol, 1.5 equiv.) were mixed in
1,4-dioxane (2 mL) and the mixture was flushed with argon for 10
minutes. Pd.sub.2(dba).sub.3 (11 mg, 0.012. mmol, 054 equiv.) and
X-Phos (11 mg, 0.022 mmol, 0.10 equiv.) were added and the reaction
mixture was flushed with argon for another 10 minutes before the
reaction was stirred for 16 h at +90.degree. C. under an atmosphere
of Argon. The reaction mixture was diluted with CH.sub.2Cl.sub.2,
filtered and evaporated. The residue was taken up in
CH.sub.2Cl.sub.2 and the organic phase was washed with H.sub.2O.
Residual water was removed from the organic phase by addition of
absolute EtOH before evaporation. The crude of the product was
purified by flash chromatography (gradient from 100%
CH.sub.2Cl.sub.2 to 5% MeOH in CH.sub.2Cl.sub.2) to yield a solid
(48 mg, 60%).
[0844] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.81 (s, 1H)
8.54 (d, 1H) 8.34 (t, 1H) 7.92 (dd, 1H) 7.59-7.52 (m, 2H) 7.43 (t,
1H) 3.93 (s, 3H) 3.85 (s, 3H) 2.41 (s, 3H); MS (ESI) m/z 340
(M-1).
Example 60
3-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-N-(3-meth-
oxypropyl)benzamide hydrochloride
##STR00120##
[0846] The title compound was prepared in accordance with the
general method G using flash chromatography (gradient from 100%
EtOAc to 5% MeOH in EtOAc) for purification. Using methyl
3-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}benzoa-
te (44.5 mg, 0.13 mmol, obtained from Example 59),
Al(CH.sub.3).sub.3 (94 mg, 1.3 mmol, 2.0 M in toluene) and
3-methoxypropan-1-amine (68.9 mg, 0.78 mmol), the base of the title
compound (26 mg, 46%) was obtained as a solid. The hydrochloride
was prepared in accordance with the method described within general
method D.
[0847] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.97 (s, 1H)
8.76 (d, 1H) 8.45-8.38 (m, 1H) 8.19 (d, 1H) 8.13 (t, 1H) 7.83-7.76
(m, 1H) 7.47 (d, 1H) 7.39 (t, 1H) 4.02 (s, 3H) 3.39-3.29 (m, 4H)
3.24 (s, 3H) 2.67 (s, 3H) 1.80-1.71 (m, 2H); MS (ESI) m/z 399
(M+1).
Example 61
[4-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2-(trifl-
uoromethoxy)phenyl]-(4-methylpiperazin-1-yl)methanone
hydrochloride
##STR00121##
[0849] The title compound was prepared in accordance with the
general method G using flash chromatography (gradient from 100%
dichloromethane to 10% MeOH in dichloromethane) for purification.
Using methyl
4-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}-2-(tr-
ifluoromethoxy)benzoate (obtained from Example 61(b)) (33 mg, 0.078
mmol), Al(CH.sub.3).sub.3 (56 mg, 0.78 mmol, 2.0 M in toluene) and
1-methylpiperazine (47 mg, 0.47 mmol), the base of the title
compound (18 mg, 40%) was obtained as a solid. The hydrochloride
was prepared in accordance with th method described within general
method D.
[0850] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.34 (s,
1H) 8.82 (d, 1H) 8.16 (d, 1H) 7.91 (s, 1 E11) 7.83 (dd, 1H) 7.49
(d, 1H) 4.03 (s, 3H) 3.09-2.87 (m, 4H) 2.80 (s, 3H) 2.66 (s, 3H);
MS (ESI) m/z 493 (M+1).
Example 61(a) Methyl 4-bromo-2-(trifluoromethoxy)benzoate
##STR00122##
[0852] 4-Bromo-1-iodo-2-(trifluoromethoxy)benzene (0.340 g, 0.93
mmol), Pd(OAc).sub.2 (0.011 g, 0.049 mmol), dppp (0.020 g, 0.048
mmol) and triethylamine (0.218 g, 2.15 mmol) were suspended in MeOH
(10 mL) in a 300 mL glass vessel. The vessel was evacuated and
filled with nitrogen gas (repeated 3 times) followed by evacuation
and filling with CO gas (repeated 2 times) to establish a
homogenous CO gas atmosphere at 3.5 bar. Heating in an oil bath at
+65.degree. C. for 90 minutes resulted in 50% conversion of the
start material as juged by GCMS. After addition of more
Pd(OAc).sub.2 (0.009 g, 0.040 mmol), dppp (0.018 g, 0.044 mmol) and
triethylamine (0.58 g, 0.57 mmol) CO gas atmosphere was established
as described above and the reaction was continued at +65.degree. C.
for another 130 minutes. When the mixture was cool (r.t) it was
filtered through diatomaceous earth and the solvent was evaporated.
The crude product was purified by flash chromatography (gradient
from 100% heptane to 20% EtOAc in heptane) to give the title
compound as a clear liquid (0.068 g, 24.5%).
[0853] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.92-7.85
(m, 1H) 7.84-7.76 (m, 2H) 3.85 (s, 3H); MS (CI) m/z 299 (79Br)
(M+1).
Example 61 (b) Methyl
4-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}-2-(tr-
ifluoromethoxy)benzoate
##STR00123##
[0855] The title compound was prepared in accordance with the
general method E (workup procedure A) with the exception that
purification of the crude product was done by flash chromatography
(gradient from 100% heptane to 100% EtOAc). Using
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
(obtained from Example 25(a)) (38 mg, 0.18 mmol), methyl
4-bromo-2-(trifluoromethoxy)benzoate (obtained from Example 61(a))
(64 mg, 0.21 mmol), Cs.sub.2CO.sub.3 (90 mg, 0.28 mmol),
Pd.sub.2(dba).sub.3 (8 mg, 0.009 mmol) and X-Phos (8 mg, 0.017
mmol), the title compound (33 mg, 42%) was obtained as a solid.
[0856] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.25 (s,
1H) 8.63 (d, 1H) 7.98-7.82 (m, 3H) 7.58 (d, 1H) 3.95 (s, 3H) 3.81
(s, 3H) 2.42 (s, 3H); MS (ESI) m/z 426 (M+1).
Example 62
N-[4-(Azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H--
pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine hydrochloride
##STR00124##
[0858] The title compound was prepared in accordance with the
general method E (Workup procedure C), with the exception that the
base of the product was purified by flash chromatography (gradient
from 100% DCM to 5% MeOH in DCM). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (53 mg, 0.19 mmol),
1-(4-chlorobenzoyl)azetidine (J. Org. Chem., 1974, 39(13), 1973)
(39 mg, 0.20 mmol), Cs.sub.2CO.sub.3 (95 mg, 0.29 mmol),
Pd.sub.2(dba).sub.3 (8 mg, 0.009 mmol) and X-Phos (10 mg, 0.02
mmol), the base of the title compound (52 mg, 62%) was obtained as
a solid. The hydrochloride was prepared in accordance with the
method described in general method D.
[0859] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.09 (s,
1H) 8.81 (d, 1H) 8.02 (s, 1H) 7.69 (d, 2H) 7.56 (d, 2H) 5.05-4.90
(m, 1H) 4.40-4.18 (m, 2H) 4.12-3.91 (m, 2H) 3.81 (dd, 2H) 3.16 (t,
2H) 2.78 (s, 3H) 2.30-2.07 (m, 4H) 1.92 (dd, 2H); MS (ESI) m/z 437
(M+1).
Example 63
N-{4-[(3,3-Difluoroazetidin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-methyl-1-(-
tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00125##
[0861] The title compound was prepared in accordance with the
general method E (Workup procedure C), with the exception that the
base of the product was purified by flash chromatography (gradient
from 100% CH.sub.2Cl.sub.2 to 5% MeOH in CH.sub.2Cl.sub.2). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (49 mg, 0.18 mmol),
1-(4-chlorobenzoyl)-3,3-difluoroazetidine (44 mg, 0.19 mmol),
Cs.sub.2CO.sub.3 (104 mg, 0.32 mmol), Pd.sub.2(dba).sub.3 (9 mg,
0.010 mmol) and X-Phos (10 mg, 0.02 mmol), the base of the title
compound (68 mg, 64%) was obtained as a solid. The hydrochloride
was prepared in accordance with the general method D.
[0862] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.15 (s,
1H) 8.83 (d, 1H) 8.02 (s, 1H) 7.74 (d, 2H) 7.63 (d, 2H) 5.03-4.91
(m, 1H) 5.0-4.2 (m, 4H) 3.82 (dd, 2H) 3.18 (t, 2H) 2.78 (s, 3H)
2.24-2.08 (m, 2H) 1.99-1.85 (m, 2H); MS (ESI) m/z 473 (M+1).
Example 63(a) 4-Bromo-2-(trifluoromethoxy)benzoic acid
##STR00126##
[0864] Thionyl chloride (5 mL) was added to 4-chloro-benzoic acid
(0.49 g, 3.1 mmol). After addition of 2 drops of anhydrous DMF, the
reaction mixture was refluxed for 15 minutes under an atmosphere of
nitrogen. The solvent was evaporated in vacuo and the residue was
dissolved in CH.sub.2Cl.sub.2 (5 mL). 3,3-difluoroazetidine
hydrochloride (0.42 g, 3.3 mmol)) was added followed by addition of
triethylamine (0.91 mL, 6.6 mmol). The reaction mixture was stirred
at r.t. for 15 minutes before it was diluted with CH.sub.2Cl.sub.2,
washed with i) saturated NaHCO.sub.3 (aq.) and ii) water. To the
organic phase Abs. (absolute) EtOH was added (until a clear
solution was obtained) and the solvents were evaporated i/7 vacuo
to give the title compound as a solid in 94% yield. The isolated
material was used in the next step without further
purification.
[0865] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.75-7.66
(m, 2H) 7.58-7.48 (m, 2H) 5.06-4.15 (m, 4H); MS (ESI) m/z 232
(M+1).
Example 64
5-Fluoro-N-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methyl-1-(tetrah-
ydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00127##
[0867] The title compound was prepared in accordance with the
general method E (Workup procedure C), with the exception that the
base of the product was purified by flash chromatography (gradient
from 100% CH.sub.2Cl.sub.2 to 6% MeOH in CH.sub.2Cl.sub.2) before
final purification by preparative HPLC. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (70 mg, 0.25 mmol),
4-(4-chloro-2-methylbenzyl)morpholine (obtained from Example 64(a))
(60 mg, 0.27 mmol), Cs.sub.2CO.sub.3 (136 mg, 0.42 mmol),
Pd.sub.2(dba).sub.3 (13 mg, 0.014 mmol) and X-Phos (15 mg, 0.031
mmol), the base of the title compound was prepared and transformed
into the hydrochloride in accordance with the method described
within general method D to yield (67 mg, 53%).
[0868] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.54 (br s,
1H) 9.90 (s, 1H) 8.79 (d, 1H) 8.00 (s, 1H) 7.63-7.50 (m, 2H) 7.48
(d, 1H) 5.05-4.90 (m, 1H) 4.27 (br. s., 2H) 3.98-3.75 (m, 6H)
3.11-3.24 (m, 6H, partly obscured by HDO signal) 2.78 (s, 3H) 2.38
(s, 3H) 2.24-2.07 (m, 2H) 1.92 (dd, 2H); MS (ESI) m/z 465
(M-1).
Example 64(a) 4-(4-Chloro-2-methylbenzyl)morpholine
##STR00128##
[0870] To a stirred, cooled (0.degree. C.) solution of
4-chloro-2-methylbenzaldehyde (0.23 g, 1.5 mmol) in MeOH (5 mL) was
added morpholine (0.15 g, 1.7 mmol), NaCNBH.sub.3 (0.49 g, 7.8
mmol) and HOAc (0.063 g, 1.0 mmol) and the reaction was stirred at
r.t. over night. The solvent was removed in vacuo and the crude
product was partitioned between EtOAc/1M NaHCO.sub.3 (aq.). The
organic phase was dried (Na.sub.2SO.sub.4), filtered, concentrated
and purified twice by flash chromatography (gradient from 100%
pentane to 10% EtOAc in pentane) to give the title compound as a
clear liquid (0.120 g, 35%).
[0871] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.27-7.21
(m, 2H) 7.20-7.14 (m, 1H) 3.57-3.49 (m, 4H) 3.38 (s, 2H) 2.36-2.31
(m, 4H) 2.31 (s, 3H); MS (ESI) m/z 226 (M+1).
Example 65
5-Fluoro-N-[4-(morpholin-4-ylmethyl)phenyl]-4-[3-oxan-4-yl-2-(trifluoromet-
hyl)imidazol-4-yl]-pyrimidin-2-amine hydrochloride
##STR00129##
[0873] The title compound was prepared in accordance with the
general method E and work-up procedure B. The product was purified
by flash chromatography (CH.sub.2Cl.sub.2/MeOH 20:1). Using
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-amine (obtained from Example 34(d)) (38 mg, 0.115
mmol), 4-(4-bromobenzyl)-morpholine (0.028 g, 0.11 mmol),
Cs.sub.2CO.sub.3 (75 mg, 0.23 mmol), Pd.sub.2(dba).sub.3 (8 mg,
0.0086 mmol) and X-Phos (8.2 mg, 0.017 mmol), the base of the title
compound (42 mg, 76%) was obtained as a solid. The hydrochloride
was prepared in accordance with the method described in general
method D.
[0874] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.74 (s, 1H),
8.73 (d, 1H), 7.55-7.53 (m, 3H), 7.21 (d, 2H), 4.81 (m, 1H), 3.78
(m, 2H), 3.55 (t, 4H), 3.39 (s, 2H), 3.18 (t, 2H), 2.32 (m, 4H),
2.13 (m, 2H), 1.86 (m, 2H); MS (ES) m/z 505 (M-1).
Example 66
5-Fluoro-N-{4-[(4-fluoropiperidin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00130##
[0876] To a solution of lithium
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate (obtained from Example 66(a)) (50 mg,
0.12 mmol) in anhydrous DMF (0.5 mL) was added a solution of HBTU
(56 mg, 0.15 mmol) in DMF (0.5 mL) and the mixture was shaken for 1
h at r.t. 4-Fluoropiperidine hydrochloride (22 mg, 0.16 mmol) was
then added followed by the addition of DIPEA (65 mg, 0.50 mmol) and
the reaction mixture was shaken o.n. (over night) at r.t. The crude
of the base product was purified using preparative HPLC and was
transferred into the hydrochloride in accordance with the method
described within general method D to yield the title compound (37
mg, 54%) as a solid.
[0877] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.02 (s,
1H) 8.80 (d, 1H) 8.02 (s, 1H) 7.66 (d, 2H) 7.35 (d, 2H) 4.79-5.04
(m, 2H) 3.81 (dd, 2H) 3.57 (br.s., 2H) 3.14 (t, 2H) 2.78 (s, 3H)
2.23-2.07 (m, 2H) 1.99-1.79 (m, 4H) 1.71 (br.s., 2H); MS (ESI) m/z
483 (M+1).
Example 66(a) Lithium
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate
##STR00131##
[0879] Ethyl
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate (obtained from Example 67) (1.16 g,
2.73 mmol) and LiOH x H.sub.2O (115 mg, 2.74 mmol) were slurried in
EtOH (15 mL) and H.sub.2O (4.4 mL). The slurry was heated at
+50-60.degree. C. under an atmosphere of Argon for 20 h then the
reaction mixture was allowed to stand for 6 days at r.t. The
solvents were then evaporated and the residue was slurried in
THF/H.sub.2O 9:1 and heated at +60.degree. C. for 24 h. No more
conversion of the ester was seen (LCMS). LiOH x H.sub.2O (59 mg,
1.16 mmol) was added in two portions and the slurry was heated at
+60.degree. C. for .about.20 h. Removal of the solvents in vacuo
gave the title compound as a solid (1.17 g). The isolated material
was used in amidation reactions without further purification.
[0880] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.49 (s, 1H)
8.54 (d, 1H) 7.75 (d, 2H) 7.45 (d, 2H) 7.32 (d, 1H) 5.11-4.98 (m,
1H) 3.78 (dd, 2H) 3.05 (t, 2H) 2.53 (s, 3H) 2.24-2.08 (m, 2H) 1.78
(dd, 2H); MS (ESI) m/z 398 (M+1).
Example 67
Ethyl
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5--
yl]pyrimidin-2-yl}amino)benzoate
##STR00132##
[0882] The title compound was prepared in accordance with the
general method E (Workup procedure C), with the exception that the
base of the product was purified by flash chromatography (gradient
from 100% CH.sub.2Cl.sub.2 to 5% MeOH in CH.sub.2Cl.sub.2). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (794 mg, 2.86 mmol), ethyl
4-iodobenzoate (820 mg, 2.97 mmol), Cs.sub.2CO.sub.3 (1.48 g, 4.54
mmol), Pd.sub.2(dba).sub.3 (59 mg, 0.064 mmol) and X-Phos (63 mg,
0.13 mmol), the title compound (1.16 g, 95%) was obtained as a
solid.
[0883] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.97 (s, 1H)
8.64 (d, 1H) 7.86 (d, 2H) 7.76 (d, 2H) 7.35 (d, 1H) 5.08-4.96 (m,
1H) 4.27 (q, 2H) 3.81 (dd, 2H) 3.12 (t, 2H) 2.54 (s, 3H) 2.27-2.11
(m, 2H) 1.82 (dd, 2H) 1.30 (t, 3H); MS (ESI) m/z 426 (M+1).
Example 68
N,N-Diethyl-4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imida-
zol-5-yl]pyrimidin-2-yl}amino)benzamide hydrochloride
##STR00133##
[0885] To a solution of lithium
4-({5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]py-
rimidin-2-yl}amino)benzoate (obtained from Example 66(a)) (50 mg,
0.12 mmol) in anhydrous DMF (0.5 mL) was added a solution of HBTU
(56 mg, 0.15 mmol) in DMF (0.5 mL) and the mixture was shaken for 1
h at r.t. Diethyl amine (13 mg, 0.18 mmol) was then added followed
by the addition of DIPEA (48 mg, 0.37 mmol) and the reaction
mixture was shaken over night. at r.t. The crude of the base
product was purified using preparative HPLC and was transferred
into the hydrochloride in accordance with the method described in
the general method D to yield the title compound (34 mg, 56%) as a
solid.
[0886] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.99 (s, 1H)
8.81 (d, 1H) 8.03 (s, 1H) 7.66 (d, 2H) 7.29 (d, 2H) 5.05-4.92 (m,
1H) 3.82 (dd, 2H) 3.16 (t, 3H) 2.78 (s, 3H) 2.24-2.08 (m, 2H)
1.97-1.86 (m, 2H) 1.10 (t, 6H); MS (ESI) m/z 453 (M+1).
Examples 69-91
[0887] The following Examples were prepared according to the
procedure described in Examples 66 and 68 except that the quantity
of DIPEA used in each case was adjusted depending on whether the
starting amine was a free base, mono- or higher salt. 3 equivalents
of DIPEA were used for amines that were freebases and one
additional equivalent was added for every additional salt. The
group R is an amine connected via the nitrogen to form an
amide.
##STR00134##
TABLE-US-00001 Ex R NMR Yield M/z 69 ##STR00135## .sup.1H NMR (400
MHz, DMSO-d.sub.6).delta. ppm 9.78 (s, 1 H) 8.61 (d, 1 H)8.26 (t, 1
H) 7.80-7.72 (m, 2 H) 7.70-7.63 (m, 2 H) 7.34 (d, 1H) 5.08-4.97 (m,
1 H) 3.81 (dd,2 H) 3.23 (s, 3 H) 3.08 (t, 2 H)2.54 (s, 3 H)
2.25-2.11 (m, 2 H)1.80 (dd, 2 H) 1.78-1.69 (m, 2 H) 67% 469 70
##STR00136## 9.80 (s, 1 H) 8.61 (d, 1 H) 7.68(d, 2 H) 7.55-7.43 (m,
2 H)7.34 (d, 1 H) 5.33 (dd, 1 H)5.08-4.94 (m, 1 H) 3.90-3.50(m, 6-7
H uncertain integral)3.17-3.04 (m, 2 H) 2.54 (s, 3 H)2.25-1.95 (m,
4 H) 1.86-1.75 (m, 2 H) 67% 469 71 ##STR00137## 9.82 (s, 1 H) 8.61
(d, 1 H) 7.70(d, 2 H) 7.50 (d, 2 H) 7.34 (d, 1H) 5.07-4.94 (m, 1 H)
3.89 (t, 2H) 3.82 (dd, 2 H) 3.71 (t, 2 H)3.11 (t, 2 H)2.54 (s, 3H)
2.5-2.37(m, 2 H) 2.24-2.11 (m, 2 H) 1.81(dd, 2 H) 73% 487 72
##STR00138## 9.78 (s, 1 H) 8.61 (d, 1 H) 8.08(d, 1 H) 7.81-7.75 (m,
2 H)7.71-7.64 (m, 2 H) 7.34 (d, 1H) 5.07-4.95 (m, 1 H) 4.04-3.92(m,
1 H) 3.91-3.84 (m, 2 H)3.81 (dd, 2 H) 3.10 (t, 2 H)2.54 (s, 3 H)
2.25-2.11 (m, 2 H)1.86-1.69 (m, 4 H) 1.63-1.50(m, 2 H). 27 of 29
signalsreported, signals obscured by HDO 48% 481 73 ##STR00139##
9.78 (s, 1 H) 8.60 (d, 1 H) 7.68(d, 2 H) 7.38-7.30 (m, 3
H)5.07-4.95 (m, 1 H) 3.82 (dd, 2H) 3.63 (br. s., 2 H) 3.11 (t, 2
H)2.84 (t, 2 H) 2.53 (s, 3 H) 2.24-2.11(m, 2 H) 1.80 (dd, 2 H) 55%
464 74 ##STR00140## 9.72 (s, 1 H) 8.59 (d, 1 H) 7.64(d, 2 H) 7.33
(d, 1 H) 7.30 (d, 2H) 5.06-4.94 (m, 1 H) 4.75 (t, 1H) 3.83 (dd, 2
H) 3.53 (br. s., 2H) 3.11 (t, 2 H) 2.53 (s, 3 H)2.24-2.10 (m, 2 H)
1.80 (dd, 2H) 1.15-1.00 (m,3 H) 33% 469 75 ##STR00141## 9.74 (s, 1
H) 8.60 (d, 1 H) 7.64(d, 2 H)7.39-7.28 (m, 3 H)5.07-4.94 (m, 1 H)
4.81-4.71(m, 1 H) 3.82 (dd, 2 H) 3.54 (br.s., 2 H) 3.11 (t, 2 H)
2.96 (s, 3H) 2.54 (s, 3 H) 2.24-2.10 (m, 2H) 1.80 (dd, 2 H) 35% 455
76 ##STR00142## 9.76 (s, 1 H) 8.59 (d, 1 H) 7.69-7.63(m, 2 H)
7.36-7.28 (m, 3H) 5.06-4.94 (m, 1 H) 3.81 (dd,2 H) 3.55-3.40 (m, 6
Huncertain integral) 3.22 (s, 3 H)3.09 (t, 2 H) 2.53 (s, 3 H)
2.42(br. s., 3 H uncertain integral)2.24-2.10 (m, 2 H) 1.79 (dd, 2
H) 64% 524 77 ##STR00143## 9.79 (s, 1 H) 8.61 (d, 1 H) 8.23-8.12(m,
1 H) 7.79-7.71 (m, 2H) 7.70-7.64 (m, 2 H) 7.34 (d,1 H) 5.08-4.97
(m, 1 H) 3.81(dd, 2 H) 3.08 (t, 2 H) 2.54 (s, 3H) 2.38 (br s, 4 H
uncertainintegral) 2.24-2.11 (m, 2 H)1.80 (dd, 2 H) 1.55-1.43 (m,
4H) 1.42-1.31 (m, 2 H) 73% 508 78 ##STR00144## 9.80 (s, 1 H) 8.61
(d, 1 H) 8.24-8.14(m, 1 H) 7.79-7.71 (m, 2H) 7.70-7.63 (m, 2 H)
7.34 (d,1 H) 5.08-4.97 (m, 1 H) 3.81(dd, 2 H) 3.62-3.51 (m, 4
H)3.07 (t, 2 H) 2.54 (s, 3 H)2.5-2.34 (m, 6 H uncertain
integral)2.24-2.11 (m, 2 H) 1.80 (dd, 2 H) 56% 510 79 ##STR00145##
9.76 (s, 1 H) 8.61 (d, 1 H) 7.99(d, 1 H) 7.77 (d, 2 H) 7.66( d, 2H)
7.35 (d, 1 H) 5.07-4.95 (m,1 H) 4.14-4.01 (m, 1 H) 3.81(dd, 2 H)
3.10 (t, 2 H) 2.54 (s, 3H) 2.25-2.10 (m, 2 H) 1.80 (dd,2 H) 1.15
(d, 6 H) 51% 439 80 ##STR00146## 9.79 (s, 1 H) 8.61 (d, 1 H)
8.30(d, 1 H) 7.79 (d, 2 H) 7.68 (d, 2H) 7.34 (d, 1 H) 5.07-4.95
(m,1 H) 4.48-4.39 (m, 1 H)3.89-3.76 (m, 4 H) 3.74-3.66 (m, 1H) 3.56
(dd, 1 H) 3.10 (t, 2 H)2.54 (s, 3 H) 2.25-2.08 (m, 3 H)1.95-1.85
(m, 1 H)1.80 (dd, 2 H) 51% 467 81 ##STR00147## 9.74 (s, 1 H) 8.60
(d, 1 H) 7.66(d, 2 H) 7.37-7.26 (m, 3 H)5.07-4.94 (m, 1 H) 3.82
(dd, 2H) 3.78-3.55 (m, 6 H) 3.50(br.s., 2 H) 3.10 (t, 2 H) 2.53
(s,3 H) 2.24-2.10 (m, 2 H) 1.80(dd, 2H) 1.91-1.67 (m, 2 H) 68% 481
82 ##STR00148## 9.76 (s, 1 H) 8.59 (d, 1 H) 7.66(d, 2 H) 7.36-7.27
(m, 3 H5.06-4.94 (m, 1 H) 3.81 (dd, 2H) 3.47 (m, 4 H) 3.09 (t, 2
H)2.53 (s, 3 H) 2.43-2.26 (m, 6 H)2.24-2.10 (m, 2 H) 1.79 (dd, 2H)
0.99 (t, 3 H) 68% 494 83 ##STR00149## 9.78 (s, 1 H) 8.60 (d, 1 H)
7.67(d, 2 H) 7.38-7.27 (m, 3 H)5.07-4.96 (m, 1 H) 3.81 (dd, 2H)
3.57-3.47 (m, 2 H) 3.08 (t, 2H) 2.53 (s, 3 H) 2.24-2.10 (m, 2H)
1.79 (dd, 2 H) 1.06 (br. s., 6 H) 44% 495 84 ##STR00150## 9.79 (s,
1 H) 8.61 (d, 1 H) 8.23(q, 1 H) 7.78-7.72 (m, 2 H)7.69-7.64 (m, 2
H) 7.34 (d, 1H) 5.08-4.96 (m, 1 H) 3.81 (dd,2 H) 3.08 (t, 2 H)
[2.76 (s, 1.5 H)2.75 (s, 1.5 H)] rot. 2.54 (s, 3 H)2.24-2.11 (m, 2
H) 1.80 (dd, 2 H 23% 411 85 ##STR00151## 9.77 (s, 1 H) 8.60 (d, 1
H) 7.66(d, 2 H) 7.50-7.40 (m, 2 H)7.33 (d, 1 H) 5.07-4.95 (m, 1H)
4.95 (dd, 1 H) 4.35-4.18 (m,1 H) 3.88-3.76 (m, 2 H)
3.65-3.20(multiplets partly obscuredby HDO-signal, no
reliableintegral) 3.11 (t, 2 H) 2.54 (s, 3 H)2.25-2.10 (m, 2 H)
1.99-1.72 (m, 4 H) 36% 467 86 ##STR00152## 9.79 (s, 1 H) 8.61 (d, 1
H) 8.24(t, 1 H) 7.81-7.75 (m, 2 H)7.71-7.65 (m, 2 H) 7.35 (d, 1
H)5.07-4.96 (m, 1 H) 4.70 (t, 1 H)3.82 (dd, 2 H) 3.53-3.45 (m, 3H)
3.10 (t, 2 H) 2.54 (s, 3 H)2.25-2.11 (m, 2 H) 1.81 (dd, 2 H) 53%
441 87 ##STR00153## 9.79 (s, 1 H) 8.61 (d, 1 H) 8.19(t, 1 H)
7.79-7.72 (m, 2 H)7.70-7.64 (m, 2 H) 7.34 (d, 1 H)5.08-4.96 (m, 1
H) 3.81 (dd, 2H) 3.09 (t, 2 H) 2.54 (s, 3 H)2.47-2.38 (m, 2 H)
2.26-2.11(m, 8 H) 1.80 (dd, 2 H) 60% 468 88 ##STR00154## 9.75 (s, 1
H) 8.59 (d, 1 H) 7.65(d, 2 H) 7.38-7.25 (m, 3 H)5.07-4.94 (m, 1 H)
3.81 (dd, 2H) 3.09 (t, 2 H) 2.90 (br. s., 2 H)2.53 (s, 3 H)
2.30-2.09 (m, 8 H)1.86-1.67 (m, 4 H) 1.43-1.26(m, 2 H) 67% 508 89
##STR00155## 9.80 (s, 1 H) 8.61 (d, 1 H) 8.27(t, 1 H) 7.80-7.72 (m,
2 H)7.71-7.64 (m, 2 H) 7.35 (d, 1 H)5.07-4.97 (m, 1 H) 3.81 (dd,
2H) 3.08 (t, 2 H) 2.93 (t, 2 H)2.73 (t, 2 H) 2.59 (t, 2 H) 2.54
(s,H) 2.27-2.10 (m, 4 H) 1.80(dd, 2 H) 71% 530 90 ##STR00156## 9.76
(s, 1 H) 8.60 (d, 1 H) 7.66(d, 2 H) 7.36-7.27 (m, 3 H)5.06-4.94 (m,
1 H) 3.81 (dd, 2H) 3.45 (br s not possible tointegrate) 3.09 (t, 2
H) 2.53 (s, 3H) 2.42 (br. s., 4 H) 2.24-2.10(m, 2 H) 1.79 (dd, 2 H)
0.97 (s, 3H) 0.96 (s, 3 H). Two broadoverlapping signals could not
beintegrated accurately 65% 508 91 ##STR00157## 9.73 (s, 1 H) 8.59
(d, 1 H) 7.65(d, 2 H) 7.33 (d, 1 H) 7.3 (d, 2H) 5.06-4.95 (m, 1 H)
3.81 (dd,2 H) 3.58 (br.s., 2 H) 3.43 (br.s., 2 H uncertain
integral) 3.09 (t,2 H) 2.63 (br. s., 1 H uncertainintegral) 2.53
(s, 3 H) 2.33-2.10(m, 5 H) 1.88- 1.69 (m, 4 H) 66% 494
Example 92
5-Fluoro-N-[4-(methylsulfonyl)phenyl]-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(t-
rifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00158##
[0889] The title compound was prepared in accordance with the
general method E using
5-fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-anine (66 mg, 0.2 mmol, obtained from Example
34(d)) and 4-bromophenyl methyl sulfone (47 mg, 0.2 mmol) to give
the title compound (43 mg, 44%).
[0890] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.46 (d,
J=2.27 Hz, 1H) 7.76-7.87 (m, 4H) 7.63 (d, J=3.03 Hz, 1H) 4.72-4.85
(m, 1H) 4.04 (dd, J=11.87, 4.80 Hz, 2H) 3.37-3.49 (m, 2H) 3.02 (s,
3H) 2.56-2.73 (m, 2H); MS (ESI) m/z 486 (M+1).
Example 93
N-[4-(Azetidin-1-ylcarbonyl)phenyl]-5-fluoro-4-[1-(tetrahydro-2H-pyran-4-y-
l)-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00159##
[0892] The title compound was prepared in accordance with the
general method E using
5-fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-amine (66 mg, 0.2 mmol, obtained from Example
34(d)) and 1-(4-bromobenzoyl)azetidine (obtained from 93(a)) (48
mg, 0.2 mmol) to give the title compound (48 mg, 49%).
[0893] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.46 (d,
J=2.53 Hz, 1H) 7.71 (d, J=3.03 Hz, 1H) 7.57-7.69 (m, 4H) 4.80-4.92
(m, 1H) 4.30 (d, J=44.21 Hz, 4H) 4.08 (dd, J=11.62, 4.80 Hz, 2H)
2.64-2.79 (m, 2H) 2.30-2.44 (m, 2H) 1.86 (d, J=8.84 Hz, 2H); MS
(ESI) m/z 491 (M+1).
Example 93 (a) 1-(4-Bromobenzoyl)azetidine
##STR00160##
[0895] Azetidine (275 mg, 4.82 mmol) followed by Et.sub.3N (0.66
mL, 4.8 mmol) was added dropwise to 4-bromobenzoyl chloride (1.0 g,
4.56 mmol) in DCM (10 mL). The mixture was stirred 30 min before it
was diluted with CH.sub.2Cl.sub.2, washed with saturated
NaHCO.sub.3 (aq.), water, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The crude product was purified by flash
chromatography (heptan to Heptan:EtOAc 1:4) to give the title
compound (765 mg, 70%) as a solid.
[0896] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.47-7.58 (m,
4H) 4.26 (t, J=7.83 Hz, 4H) 2.29-2.43 (m, 2H); MS (ESI) m/z 240
(M+1).
Example 94
N-[4-(Azetidin-1-ylcarbonyl)-3-chlorophenyl]-4-(1,2-dimethyl-1H-imidazol-5-
-yl)-5-fluoropyrimidin-2-amine
##STR00161##
[0898] The title compound was prepared in accordance with the
general method E using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine (26 mg,
0.125 mmol, obtained from Example 25(a)) and
1-(4-bromo-2-chlorobenzoyl)azetidine (obtained from Example 94(a))
(35 mg, 0.127 mmol) to give the title compound (17 mg, 34%).
[0899] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.46 (d,
J=2.53 Hz, 1H) 7.71 (d, J=3.03 Hz, 1H) 7.57-7.69 (m, 4H) 4.80-4.92
(m, 1H) 4.30 (d, J=44.21 Hz, 4H) 4.08 (dd, J=111.62, 4.80 Hz, 2H)
3.42 (t, J=12.00 Hz, 2H) 2.64-2.79 (m, 2H) 2.30-2.44 (m, 2H) 1.86
(d, J=8.84 Hz, 2H); MS (ESI) m/z 491 (M+1).
Example 94(a) 1-(4-Bromo-2-chlorobenzoyl)azetidine
##STR00162##
[0901] The title compound was prepared in accordance with the
general method H using 4-bromo-2-chlorobenzoic acid (0.75 g, 3.19
mmol) and azetidine (192 mg, 3.36 mmol) to give the title compound
(800 mg, 91%).
[0902] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.58 (d,
J=2.02 Hz, 1H) 7.45 (dd, J=8.08, 1.77 Hz, 1H) 7.22 (d, J=8.08 Hz,
1H) 4.22 (t, J=7.83 Hz, 2H) 3.97 (t, 2H) 2.28-2.41 (m, 2H); MS
(ESI) m/z 274 (M+1).
Example 95
N-[4-(Azetidin-1-ylcarbonyl)-3-methylphenyl]-4-(1,2-dimethyl-1H-imidazol-5-
-yl)-5-fluoropyrimidin-2-amine
##STR00163##
[0904] The title compound was prepared in accordance with the
general method E using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine (30 mg,
0.145 mmol, obtained from Example 25(a)) and
1-(4-bromo-2-methylbenzoyl)azetidine (obtained from Example 95(a))
(37 mg, 0.145 mmol) to give the title compound (32 mg, 58%).
[0905] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.27 (d,
J=3.03 Hz, 1H) 7.75 (d, J=4.29 Hz, 1H) 7.36-7.45 (m, 2H) 7.18-7.26
(m, 2H) 4.21 (t, J=7.58 Hz, 2H) 3.98 (t, J=7.58 Hz, 2H) 3.93 (s,
3H) 2.48 (s, 3H) 2.25-2.36 (m, 2H); MS (ESI) m/z 381 (M+1).
Example 95(a) 1-(4-Bromo-2-methylbenzoyl)azetidine
##STR00164##
[0907] The title compound was prepared in accordance with the
general method H using 4-bromo-2-methylbenzoic acid (1.0 g, 3.93
mmol) and azetidine (225 mg, 3.94 mmol) to give the title compound
(670 mg, 67%).
[0908] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.38-7.41 (m,
1H) 7.33 (dd, J=8.08, 1.52 Hz, 1H) 7.11 (d, J=8.08 Hz, 1H) 4.06 (d,
J=97.01 Hz, 4H) 2.38 (s, 3H) 2.27-2.36 (m, 2H); MS (ESI) m/z 254
(M+1).
Example 96
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-[4-(methylsulfonyl)phenyl]pyr-
imidin-2-amine
##STR00165##
[0910] The title compound was prepared in accordance with the
general method E using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine (40 mg,
0.193 mmol, obtained from Example 25(a)) and 4-bromophenyl methyl
sulfone (47 mg, 0.20 mmol) to give the title compound (21 mg,
30%).
[0911] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.32 (d,
J=3.03 Hz, 1H) 7.84-7.91 (m, 2H) 7.75-7.82 (m, 3H) 7.70 (s, 1H)
3.95 (s, 3H) 3.06 (s, 3H) 2.50 (s, 3H); MS (ESI) m/z 362 (M+1).
Example 97
N-[3-Chloro-4-(methylsulfonyl)phenyl]-4-(1,2-dimethyl-1H-imidazol-5-yl)-5--
fluoropyrimidin-2-amine
##STR00166##
[0913] The title compound was prepared in accordance with the
general method E using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine (40 mg,
0.193 mmol, obtained from Example 25(a)) and 4-bromo-2-chlorophenyl
methyl sulfone (obtained from 97(a)) (54 mg, 0.20 mmol) to give the
title compound (21 mg, 27%).
[0914] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.34 (d,
J=3.03 Hz, 1H) 8.10 (d, J=2.02 Hz, 1H) 8.03 (d, J=8.84 Hz, 1H) 7.85
(s, 1H) 7.79 (d, J=4.55 Hz, 1H) 7.49 (dd, J=8.72, 2.15 Hz, 1H) 3.98
(s, 3H) 3.27 (s, 3H) 2.51 (s, 3H); MS (ESI) m/z 396 (M+1).
Example 97(a) 4-Bromo-2-chlorophenyl methyl sulfone
##STR00167##
[0916] 4-Bromo-2-chlorobenzenesulfonyl chloride (960 mg, 3.3 mmol)
was added in portion to a solution of Na.sub.2SO.sub.3 (460 mg, 3.6
mmol) and NaHCO.sub.3 (555 mg, 6.6 mmol) in H.sub.2O (5 mL) at
+75.degree. C. After 2 h. at +75.degree. C. the reaction mixture
was allowed to reach r.t. and MeI (1 mL, 16 mmol) was added. The
mixture was heated in a microwave oven (+100.degree. C., 2
min).
[0917] The reaction mixture was cooled to r.t. and diluted with
CH.sub.2Cl.sub.2. The organic phase was washed with H.sub.2O, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the
title compound (450 mg, 50%)
[0918] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.02 (d,
J=8.59 Hz, 1H) 7.75 (d, J=1.77 Hz, 1H) 7.64 (dd, J=8.59, 1.77 Hz,
1H) 3.27 (s, 3H);
[0919] MS (ESI) m/z 268 (M.sup.+).
Example 98
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-4-(1,2-dimethyl-1H-
-imidazol-5-yl)-5-fluoropyrimidin-2-amine
##STR00168##
[0921] The title compound was prepared in accordance with the
general method E using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine (40 mg,
0.193 mmol, obtained from Example 25(a)) and
1-[(4-bromo-2-chlorophenyl)sulfonyl]-4-methylpiperazine (obtained
from example 52(a)) (70 mg, 0.198 mmol) to give the title compound
(29 mg, 31%).
[0922] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.34 (d,
J=3.03 Hz, 1H) 8.05 (d, J=2.02 Hz, 1H) 7.95 (d, J=8.84 Hz, 1H) 7.80
(d, J=4.55 Hz, 1H) 7.49 (s, 1H) 7.43 (dd, J=8.84, 2.27 Hz, 1H) 3.99
(s, 3H) 3.26-3.35 (m, 4H) 2.52 (s, 3H) 2.44-2.49 (m, 4H) 2.30 (s,
3H); MS (ESI) m/z 480 (M+1).
Example 99
4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoro-N-{3-methyl-4-[(4-methylpiperaz-
in-1-yl)sulfonyl]phenyl}pyrimidin-2-amine
##STR00169##
[0924] The title compound was prepared in accordance with the
general method E using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine (40 mg,
0.193 mmol, obtained from Example 25(a)) and
1-[(4-bromo-2-methylphenyl)sulfonyl]-4-methylpiperazine (obtained
from Example 53(a)) (66 mg, 0.198 mmol) to give the title compound
(32 mg, 36%).
[0925] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.34 (d,
J=3.03 Hz, 1H) 8.05 (d, J=2.02 Hz, 1H) 7.95 (d, J=8.84 Hz, 1H) 7.80
(d, J=4.55 Hz, 1H) 7.49 (s, 1H) 7.43 (dd, J=8.84, 2.27 Hz, 1H) 3.99
(s, 3H) 3.26-3.37 (m, 4H) 2.52 (s, 3H) 2.44-2.50 (m, 4H) 2.30 (s,
3H); MS (ESI) n7/z 460 (M+1).
Example 100
N-[4-(Azetidin-1-ylcarbonyl)-3-(trifluoromethoxy)phenyl]-4-(1,2-dimethyl-1-
H-imidazol-5-yl)-5-fluoropyrimidin-2-amine
##STR00170##
[0927] The title compound was prepared in accordance with the
general method E using
4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-amine (40 mg,
0.193 mmol, obtained from Example 25(a)) and
1-[4-bromo-2-(trifluoromethoxy)benzoyl]azetidine (obtained from
Example 100(c)) (64 mg, 0.197 mmol) to give the title compound (29
mg, 34%).
[0928] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.31 (d,
J=3.03 Hz, 1H) 7.72-7.79 (m, 2H) 7.65 (s, 1H) 7.45 (d, J=1.01 Hz,
2H) 4.21 (t, J=7.71 Hz, 2H) 4.05 (t, J=7.71 Hz, 2H) 2.49 (s, 3H)
2.27-2.37 (m, 2H); MS (ESI) m/z 451 (M+1).
Example 100(a) Methyl 4-bromo-2-(trifluoromethoxy)benzoate
##STR00171##
[0930] To 4-bromo-1-iodo-2-(trifluoromethoxy)benzene (2.0 g, 5.45
mmol), Pd(OAc).sub.2 (121 mg, 0.54 mmol), dppp (222 mg, 0.54 mmol)
and Et.sub.3N (2.3 mL, 16.3 mmol) in MeOH (50 mL) was introduced CO
(g) to a pressure of 2.5 bar. The mixture was stirred at 2.5 bar
and at +65.degree. C. for 4 h. The mixture was filtered through
diatomaceous earth and the residue was concentrated in vacuo. The
crude product was purified by flash chromatography (Heptan to
Heptane:EtOAc 4:1) to give the title compound (900 mg, 55%) as a
liquid.
[0931] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.86 (d,
J=8.34 Hz, 1H) 7.55 (dd, J=8.46, 1.89 Hz, I H) 7.50-7.53 (m, 1H)
3.94 (s, 3H); MS (ESI) m/z 298 (M)
Example 100(b) 4-Bromo-2-(trifluoromethoxy)benzoic acid
##STR00172##
[0933] LiOH monohydrate (75 mg, 1.79 mmol) was added to methyl
4-bromo-2-(trifluoromethoxy)benzoate (400 mg, 1.34 mmol, obtained
from 100(a)) in THF: H.sub.2O (9:1, 5 mL). The mixture was heated
in a microwave oven (+120.degree. C., 10 min). The reaction mixture
was cooled to r.t. and diluted with CH.sub.2Cl.sub.2 and H.sub.2O.
2 M HCl was added until pH 1. The mixture was extracted and the
water phase was re-extracted with CH.sub.2Cl.sub.2. The organic
phases were combined, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to give the title compound (300 mg, 79%) as a
solid.
[0934] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.99 (d,
J=8.34 Hz, 1H) 7.59 (dd, J=8.34, 1.77 Hz, 1H) 7.55-7.57 (m, J=1.26
Hz, 1H); MS (ESI) m/z 283 (M-1).
Example 100(c) 1-[4-Bromo-2-(trifluoromethoxy)benzoyl]azetidine
##STR00173##
[0936] The title compound was prepared in accordance with the
general method H using 4-bromo-2-(trifluoromethoxy)benzoic acid
(300 mg, 1.05 mmol, obtained from Example 100(b)) and azetidine (70
mg, 1.22 mmol) to give the title compound (200 mg, 59%).
[0937] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.50 (dd,
J=8.21, 1.64 Hz, 1H) 7.45-7.48 (m, 1H) 7.38 (d, J=8.08 Hz, 1H) 4.21
(t, J=7.71 Hz, 2H) 4.00 (t, J=7.58 Hz, 2H) 2.34 (dd, 18H);
[0938] MS (ESI) m/z 324 (M+1).
Example 101
5-Fluoro-N-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]-4-[3-methyl-2-(trifl-
uoromethyl)imidazol-4-yl]-pyrimidin-2-amine hydrochloride
##STR00174##
[0940] The title compound was prepared in accordance with the
general method E using
5-Fluoro-4-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (obtained from Example 101(e)) (35 mg, 0.135 mmol) and
1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (described in WO
2003004472) (38 mg, 0.12 mmol) to give (47 mg, 78%). The
hydrochloride was prepared in accordance with that described in
general method D.
[0941] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.6-10.3 (m,
2H), 8.82 (s, 1H), 7.99 (s, J=8.4 Hz, 2H), 7.9-7.7 (m, 3H), 4.13
(s, 3H), 3.8-3.6 (m, 2H), 3.5-3.3 (m, 2H), 3.3-3.0 (m, 2H), 2.73
(s, 3H), 2.7-2.5 (m, 2H); MS (ES) m/z 500 (M+1).
Example 101(a)
2,2,2-Trifluoro-N-methyl-N-(5-methylisoxazol-4-yl)acetamide
##STR00175##
[0943] Trifluoroacetic anhydride (10 mL, 71 mmol) in
CH.sub.2Cl.sub.2 (100 mL) was added to N,5-dimethylisoxazol-4-amine
(Reiter, L. A., J. Org. Chem. 1987, 52, 2714-2726) (6.68 g, 59.6
mmol) in DCM (200 mL) and pyridine (6 mL, 74 mmol) at 0.degree. C.
The mixture was stirred at 0.degree. C. for 30 min and at r.t. for
2 h. The reaction mixture was diluted with CH.sub.2Cl.sub.2 (100
mL) and washed with H.sub.2O and saturated NaHCO.sub.3 (aq). The
organic layer was dried (Na.sub.2SO.sub.4), concentrated in vacuo
to give the title compound (12.4 g, 100%) as a solid.
[0944] MS (ESI) m/z 208 (M.sup.+).
Example 101(b)
1-[1-Methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]ethanone
##STR00176##
[0946] 2,2,2-trifluoro-N-methyl-N-(5-methylisoxazol-4-yl)acetamide
(12.4 g, 59.6 mmol, obtained from Example 1(a)) in EtOH (30 ml) was
hydrogenated over Pd/C (10%, 1.0 g) at 50 psi. The reaction mixture
was stirred at +50.degree. C. overnight. Sodium methoxide (5.0 g,
87.7 mmol) was added and the resulting mixture was heated to reflux
overnight. The mixture was filtered through diatomaceous earth and
the residue was diluted with saturated NaHCO.sub.3 (aq.) and
extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was
purified by flash chromatography (Heptane:EtOAc 2:1) to give the
title compound (6.1 g, 52%) as an oil.
[0947] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.77 (s, 1H),
4.07 (s, 3H), 2.54 (s, 3H);
[0948] MS (ESI) m/z 192 (M.sup.+).
Example 101(c)
(2E)-3-(Dimethylamino)-1-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]p-
rop-2-en-1-one
##STR00177##
[0950] 1-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]ethanone
(6.0 g, 31 mmol, obtained from Example 101(b)) was dissolved in
DMFDMA/DMF (1:1, 46 mL) and the mixture was stirred at +100.degree.
C. overnight. After cooling to r.t. the mixture was diluted with
H.sub.2O and extracted with CH.sub.2Cl.sub.2 (three times). The
organic phases were combined, dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo to give the title compound (7.11 g, 93%)
as a solid.
[0951] MS (ESI) m/z 247 (M.sup.+); MS (ESI) m/z 248 (M+1).
Example 101(d)
(2Z)-3-(Dimethylamino)-2-fluoro-1-[1-methyl-2-(trifluoromethyl)-1H-imidaz-
ol-5-yl]prop-2-en-1-one
##STR00178##
[0953] Selectfluor (10.9 g, 30.8 mmol) was added in portions to a
stirred solution of
(2E)-3-(dimethylamino)-1-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]p-
rop-2-en-1-one (7.0 g, 28.3 mmol, obtained from Example 101 (c)) in
CH.sub.3CN (250 mL) at 0.degree. C. After stirring at 0.degree. C.
for 1.5 h the reaction mixture was diluted with H.sub.2O and
extracted with CH.sub.2Cl.sub.2 (three times). The organic phases
were combined, dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo to give the crude title compound that was used in the next
step without any father purification.
[0954] MS (ESI) m/z 265 (M.sup.+); MS (ESI) m/z 266 (M+1).
Example 101 (e)
5-Fluoro-4-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne
##STR00179##
[0956] A reaction mixture of
(2Z)-3-(dimethylamino)-2-fluoro-1-[1-methyl-2-(trifluoromethyl)-1H-imidaz-
ol-5-yl]prop-2-en-1-one (28 3 mmol, crude from Example 101(d)),
guanidine carbonate (13.5 g, 75 mmol) and NaOMe (6.5 g, 120 mmol)
in 1-butanol (250 mL) was heated to reflux under argon atmosphere
for 2.5 h. The mixture was diluted with H.sub.2O and extracted with
CH.sub.2Cl.sub.2. The organic phases were combined, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude
product was purified by flash chromatography (Heptane:EtOAc 1:1 to
Heptane:EtOAc 1:2) to give the title compound (1.76 g, 21%) as a
solid.
[0957] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.27 (d,
J=3.03 Hz, 1H) 7.74 (d, J=4.04 Hz, 1H) 5.02 (br. s., 2H) 4.14 (s,
3H); MS (ESI) m/z 261 (M.sup.+).
Example 102
5-Fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-N-[4-(morpholin-4-y-
lmethyl)phenyl]-pyrimidin-2-amine hydrochloride
##STR00180##
[0959] The title compound was prepared in accordance with the
general method E using
5-fluoro-4-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (obtained from Example 101(e)) (35 mg, 0.135 mmol) and
4-(4-bromobenzyl)-morpholine (34 mg, 0.134 mmol) to give (48 mg,
83%). The hydrochloride was prepared in accordance to that
described in general method D.
[0960] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.95 (br s,
1H), 10.00 (s, 1H), 8.73 (s, 1H), 7.9-7.7 (m, 3H), 7.52 (d, J=8.4
Hz, 2H), 4.26 (d, J=4 Hz, 2H), 4.10 (s, 3H), 3.93 (d, J=12 Hz, 2H),
3.77 (d, J=12 Hz, 2H), 3.23 (d, J=12 Hz, 2H), 3.1-3.0 (m, 2H); MS
(ESI) m/z 437 (M+1)
Example 103
[4-[5-Fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-pyrimidin-2-yl]-
aminophenyl]-(4-methylpiperazin-1-yl)-methanone hydrochloride
##STR00181##
[0962] The title compound was prepared in accordance with the
general method E using
5-fluoro-4-[1-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (obtained from Example 101(e)) (35 mg, 0.135 mmol) and
1-(4-bromobenzoyl)-4-methylpiperazine (36 mg, 0.127 mmol) to give
(30 mg, 51% yield). The hydrochloride was prepared in accordance to
that described in general method D.
[0963] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.84 (br s,
1H), 10.10 (s, 1H), 8.76 (s, 1H), 7.9-7.7 (m, 3H), 7.45 (d, J=8.4
Hz, 2H), 4.2-4.0 (m, 5H), 3.6-3.2 (m), 3.2-3.0 (m, 2H), 2.77 (s,
3H); hydrogens in the region 3.6-3.2 ppm were not integrated due to
the overlap with the water peak; MS (ESI) m/z 464 (M+1)
Example 104
[4-[5-Fluoro-4-[3-tetrahydropyran-4-yl-2-(trifluoromethyl)imidazol-4-yl]-p-
yrimidin-2-yl]aminophenyl]-(4-methylpiperazin-1-yl)-methanone
hydrochloride
##STR00182##
[0965] The title compound was prepared in accordance with the
general method E and work-up procedure B. The product was purified
by flash chromatography (CH.sub.2Cl.sub.2/MeOH 30:1, 20:1 then
15:1). Using
5-fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-1H-imidazol--
5-yl]pyrimidin-2-amine (obtained from Example 34(d)) (33 mg, 0.1
mmol), 1-(4-bromobenzoyl)-4-methylpiperazine (0.027 g, 0.095 mmol),
Cs.sub.2CO.sub.3 (65 mg, 0.2 mmol), Pd.sub.2(dba).sub.3 (6.8 mg,
0.0075 mmol) and X-Phos (7 mg, 0.015 mmol), the base of the title
compound (35 mg, 70%) was obtained as a solid. The hydrochloride
was prepared in accordance with the method described in general
method D.
[0966] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.60 (br s,
1H), 10.11 (s, 1H), 8.82 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.56 (s,
1H), 7.42 (d, J=8.4 Hz, 2H), 4.80 (t, 1H), 3.80 (d, J=8.4 Hz, 2H),
3.22 (t, J=11.5 Hz, 2H), 3.2-3.0 (m, 2H), 2.78 (s, 3H), 2.2-2.1 (m,
2H), 2.0-1.8 (m, 2H); 6 Hydrogens were not assigned in the region
3.6-2.2 ppm due to the presence of the water and DMSO peaks in this
region; MS (ESI) m/z 534.5 (M+1); MS (ESI) m/z 532.5 (M-1).
Example 105
5-Fluoro-N-[3-(methylsulfonyl)-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methyl-
-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00183##
[0968] The title compound was prepared in accordance with the
general method E (Workup procedure C), with the exception that the
base of the product was purified by flash chromatography (gradient
from 100% CH.sub.2Cl.sub.2 to 6% MeOH in CH.sub.2Cl.sub.2) before
final purification by preparative HPLC. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (35 mg, 0.13 mmol),
4-[4-bromo-2-(methylsulfonyl)benzyl]morpholine (obtained from
Example 105(a)) (46 mg, 0.14 mmol), Cs.sub.2CO.sub.3 (66 mg, 0.20
mmol), Pd.sub.2(dba).sub.3 (6 mg, 0.006 mmol) and X-Phos (8 mg,
0.017 mmol), the base of the title compound (23 mg, 32%) was
obtained as a solid. The hydrochloride was prepared in accordance
with the method described in general method D.
[0969] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.47
(br.s., 1H) 10.40 (s, 1H) 8.88 (d, 1H) 8.33 (s, 1H) 8.22 (d, 1H)
8.07 (s, 1H) 7.98 (br.s., 1H) 5.00-4.87 (m, 1H) 4.62 (br.s., 2H)
4.03-3.72 (m, 6H) 2.82 (s, 3H) 2.24-2.09 (m, 2H) 2.02-1.90 (m, 2H)
additional protons obscured by the HDO signal; MS (ESI) m/z 531
(M+1).
Example 105(a) 4-[4-Bromo-2-(methylsulfonyl)benzyl]morpholine
##STR00184##
[0971] To a stirred solution of
4-bromo-2-(methylsulfonyl)benzaldehyde (0.20 g, 0.76 mmol) in MeOH
(1.5 mL) was added morpholine (0.073 g, 0.84 mmol), NaCNBH.sub.3
(0.072 g, 1.1 mmol) and HOAc (0.091 g, 1.5 mmol) and the reaction
was stirred at r.t. over night. The solvent was removed in vacuo
and the crude product was partitioned between EtOAc/1M NaHCO.sub.3
(aq.). The organic phase was dried (Na.sub.2SO.sub.4), filtered
concentrated and purified by flash chromatography (gradient from
100% heptane to 40% EtOAc in heptane) to give the title compound as
a solid (0.088 g, 35%).
[0972] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.03 (d, 1H)
7.90 (dd, 1H) 7.56 (d, 1H) 3.82 (s, 2H) 3.59-3.51 (m, 4H) 3.48 (s,
3H) 2.44-2.35 (m, 4H); MS (ESI) m/z 336 (+1).
Example 106
5-Fluoro-N-[4-(methylsulfonyl)-3-(trifluoromethyl)phenyl]-4-[2-methyl-1-(t-
etrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
hydrochloride
##STR00185##
[0974] The title compound was prepared in accordance with the
general method E (Workup procedure C), with the exception that the
base of the product was purified by flash chromatography (gradient
from 100% EtOAc to 10% MeOH in EtOAc). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (40 mg, 0.14 mmol),
4-bromo-1-(methylsulfonyl)-2-(trifluoromethyl)benzene (43 mg, 0.14
mmol), Cs.sub.2CO.sub.3 (85 mg, 0.26 mmol), Pd.sub.2(dba).sub.3 (8
mg, 0.009 mmol) and X-Phos (9 mg, 0.018 mmol), the base of the
title compound (64 mg, 83%) was obtained as a solid. The
hydrochloride was prepared in accordance with the method described
within general method D.
[0975] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.64 (s,
1H) 8.94 (d, 1H) 8.30-8.21 (m, 2H) 8.16-8.01 (m, 2H) 4.99-4.87 (m,
1H) 3.84 (dd, 2H) 3.23 (s, 3H) 3.28-3.20 (m, 2H signal partly
obscured by the HDO signal) 2.80 (s, 3H) 2.24-2.09 (m, 2H) 1.94
(dd, 2H); MS (ESI) m/z 500 (M+1).
Example 107
6-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyr-
imidin-2-yl}amino)-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide
hydrochloride
##STR00186##
[0977] The title compound was prepared in accordance with the
general method E (Workup procedure C), with the exception that the
base of the product was purified by flash chromatography twice [(i)
gradient from 100% EtOAc to 10% MeOH in EtOAc, (ii) gradient from
heptane/CH.sub.2Cl.sub.2 7:3 to 3% MeOH in heptane/CH.sub.2Cl.sub.2
7:3] followed by precipitation from a solution in
MeOH/CH.sub.2Cl.sub.2 1:3 by addition of toluene. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (51 mg, 0.18 mmol),
6-chloro-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide (46 mg, 0.20
mmol), Cs.sub.2CO.sub.3 (95 mg, 0.29 mmol), Pd.sub.2(dba).sub.3 (9
mg, 0.010 mmol) and X-Phos (10 mg, 0.021 mmol), the base of the
title compound (20 mg, 23%) was obtained as a solid. The
hydrochloride was prepared in accordance with the method described
in general method D with the exception that the salt was
precipitated from a CH.sub.3CN/CH.sub.2Cl.sub.2 solution.
[0978] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.45 (s,
1H) 8.89 (d, 1H) 8.26 (d, 1H) 8.21 (dd, 1H) 8.03 (br. s., 1H) 7.89
(d, 1H) 5.03-4.90 (m, 1H) 3.95 (t, 2H) 3.82 (dd, 2H) 3.26-3.21 (m,
2H signal partly obscured by the HDO signal) 3.16 (t, 2H) 2.79 (s,
3H) 2.23-2.08 (m, 2H) 1.93 (dd, 2H); MS (ESI) m/z 470 (M-1).
Example 108
6-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyr-
imidin-2-yl}amino)thiochroman-4-ol 1,1-dioxide hydrochloride
##STR00187##
[0980] The title compound was prepared in accordance with the
general method E (Workup procedure C), with the exception that the
base of the product was purified by flash chromatography (gradient
from 100% CH.sub.2Cl.sub.2 to 5% MeOH in CH.sub.2Cl.sub.2). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (52 mg, 0.18 mmol),
6-chlorothiochroman-4-ol 1,1-dioxide (Boissier, Jacques R.;
Ratouis, Roger, Fr. M. (1970), FR 7499) (46 mg, 0.20 mmol),
Cs.sub.2CO.sub.3 (95 mg, 0.29 mmol), Pd.sub.2(dba).sub.3 (8 mg,
0.009 mmol) and X-Phos (9 mg, 0.019 mmol), the base of the title
compound (10 mg, 12%) was obtained as a solid. The hydrochloride
was prepared in accordance with the general method D.
[0981] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.19 (s,
1H) 8.83 (d, 1H) 7.98 (br. s., 1H) 7.87 (dd, 1H) 7.79 (d, 1H) 7.66
(d, 1H) 5.81 (br s, 1H) 5.05-4.90 (m, 1H) 4.76-4.66 (m, 1H) 3.83
(dd, 2H) 3.60-3.45 (m, 2H) 3.14 (q, 2H) 2.76 (s, 3H) 2.5-2.40 (m,
1H) 2.36-2.23 (m, 1H) 2.23-2.07 (m, 2H) 1.98-1.85 (m, 2H); MS (ESI)
m/z 474 (M+1).
Example 109
N-(3-Dimethylaminopropyl)-3-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrim-
idin-2-yl]amino]benzamide
##STR00188##
[0983] The title compound was prepared in accordance with the
general method G using preparative HPLC (gradient from 0% to 40%
acetonitrile in ammonium acetate buffer) for purification. Using
methyl
3-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}benzoa-
te (44 mg, 0.129 mmol, obtained from Example 59),
Al(CH.sub.3).sub.3 (54 mg, 0.75 mmol, 2.0 M in toluene) and
N,N-dimethylpropane-1,3-diamine (0.89 mg, 0.87 mmol), the title
compound (45 mg, 84%) was obtained as a solid.
[0984] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.70 (s, 1H)
8.53 (d, 1H) 8.42 (t, 1H) 8.12 (s, 1H) 7.82-7.75 (m, 1H) 7.56 (d,
1H) 7.43-7.32 (m, 2H) 3.92 (s, 3H) 2.40 (s, 3H) 2.25 (t, 2H) 2.13
(s, 6H) 1.71-1.58 (m, 2H); MS (ESI) m/z 412 (M+1).
Example 110
N-(3-Dimethylaminopropyl)-3-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrim-
idin-2-yl]amino]-N-methyl-benzamide hydrochloride
##STR00189##
[0986] The title compound was prepared in accordance with the
general method G using preparative HPLC (gradient from 5% to 45%
acetonitrile in ammonium acetate buffer) for purification. Using
methyl
3-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}benzoa-
te (51 mg, 0.149 mmol, obtained from Example 59),
Al(CH.sub.3).sub.3 (107 mg, 1.49 mmol, 2.0 M in toluene) and
N,N',N'-trimethylpropane-1,3-diamine (0.89 mg, 0.87 mmol), the base
of the title compound (38 mg, 51%) was obtained as a solid. The
hydrochloride was prepared in accordance with the method described
in general method D.
[0987] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.32 (br.
s., 1H) 9.99 (br. s., 1H) 8.76 (d, 1H) 8.17 (d, 1H) 7.79-7.68 (m,
2H) 7.39 (t, 1H) 7.06 (br. s., 1H) 4.02 (s, 3H) 3.56-3.47 (m, 2H)
3.13-3.02 (m, 2H) 2.94 (br. s., 3H) 2.77 (br. s., 6H) 2.67 (s, 6H)
2.05-1.93 (m, 2H); MS (ESI) m/z 426 (M+1).
Example 111
[3-[[4-(2,3-Dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]-[-
3-(hydroxymethyl)-1-piperidyl]methanone
##STR00190##
[0989] The title compound was prepared in accordance with the
general method G using preparative HPLC (gradient from 10% to 50%
acetonitrile in ammonium acetate buffer) for purification. Using
methyl
3-{[4-(1,2-dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}benzoa-
te (53 mg, 0.155 mmol, obtained from Example 59),
Al(CH.sub.3).sub.3 (108 mg, 1.50 mmol, 2.0 M in toluene) and
3-piperidylmethanol (0.102 mg, 0.89 mmol), the title compound (56
mg, 85%) was obtained as a solid.
[0990] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.96 (s, 1H)
8.75 (d, 1H) 8.16 (d, 1H) 7.70 (s, 1H) 7.71 (d, 1H) 7.37 (t, 1H)
6.98 (d, 1H) 4.01 (s, 3H) 3.72 (br. s., 1H) 3.02-2.90 (m, 1H)
2.83-2.69 (m, 1H) 2.66 (s, 3H) 1.78-1.68 (m, 2H) 1.58 (br. s., 2H)
1.41 (br. s., 1H) 1.27-1.12 (m, 1H); MS (ESI) m/z 425 (M+1).
Example 112
N-{3-Chloro-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-5-fluoro-4-[2-meth-
yl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00191##
[0992] The title compound was prepared in accordance with the
general method E (Workup procedure C). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (33.1 mg, 0.119 mmol),
1-(2,4-dichlorobenzoyl)-4-methylpiperazine (33.0 mg, 0.120 mmol),
Cs.sub.2CO.sub.3 (62.0 mg, 0.190 mmol), Pd.sub.2(dba).sub.3 (6.0
mg, 0.0065 mmol) and X-Phos (7.0 mg, 0.015 mmol), the title
compound was obtained (34.1 mg, 56%).
[0993] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.89 (s, 1H)
8.65 (d, 1H) 7.85 (d, 1H) 7.61 (dd, 1H) 7.35 (d, 1H) 7.25 (d, 1H)
4.92-5.08 (m, 1H) 3.57-3.67 (m, 2H) 3.13-3.18 (m, 2H) 3.08-3.13 (m,
2H) 2.55 (s, 3H) 2.30-2.41 (m, 4H) 2.22-2.28 (m, 4H) 2.19 (s, 3H)
1.83 (d, 2H); MS (ESI) m/z 514 (M+1).
Example 113
5-Fluoro-N-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-4-[2-methyl-1-(tet-
rahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00192##
[0995] The title compound was prepared in accordance with the
general method E (Workup procedure C). Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (32.3 mg, 0.116 mmol),
1-(3-chlorobenzoyl)-4-methylpiperazine (28.0 mg, 0.117 mmol),
Cs.sub.2CO.sub.3 (60.0 mg, 0.184 mmol), Pd.sub.2(dba).sub.3 (6.0
mg, 0.0065 mmol) and X-Phos (7.0 mg, 0.015 mmol), the title
compound was obtained (31.0 mg, 56%).
[0996] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.67 (s, 1H)
8.59 (d, 1H) 7.69 (d, 1H) 7.66-7.63 (m, 11H) 7.34-7.30 (m, 21H)
6.97 (d, 1H) 3.86-3.78 (m, 2H) 3.12 (t, 21H) 2.53 (s, 3H) 2.36-2.20
(m, 41H) 2.16 (s, 3H) 2.20-2.08 (m, 4H) 1.83-1.74 (m, 2H); MS (ESI)
m/z 480 (M+1).
Example 114
(4-{[4-(1,2-Dimethyl-1H-imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino}phenyl-
)(pyridin-2-yl)methanol
##STR00193##
[0998]
{4-[4-(2,3-Dimethyl-3H-imidazol-4-yl)-pyrimidin-2-ylamino]-phenyl}--
pyridin-2-yl-methanone (obtained from Example 31) (10 mg, 0.025
mmol) was treated with NaBH.sub.4 (10 mg, 0.264 mmol) in EtOH (2
mL) at 0.degree. C. The crude material was directly purified by
preparative HPLC to give the title compound (2 mg, 20%).
[0999] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.59 (d,
J=4.80 Hz, 1H) 8.25 (d, J=3.28 Hz, 1H) 7.73 (d, J=4.29 Hz, 1H)
7.60-7.68 (m, 1H) 7.52 (d, J=8.34 Hz, 2H) 7.35 (d, J=8.59 Hz, 2H)
7.20-7.25 (m, 1H) 7.17 (d, J=7.83 Hz, 1H) 7.05 (br. s., 1H) 5.75
(s, 1H) 5.30 (br. s., 1H) 3.90 (s, 3H) 2.48 (s, 3H); MS (ES) m/z
391 (M+1).
Example 115
5-Fluoro-N-[4-(isopropylsulfonyl)phenyl]-4-[2-methyl-1-(tetrahydro-2H-pyra-
n-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00194##
[1001] The title compound was prepared in accordance with the
general method E. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-anine (obtained from Example 7(e)) (0.05 g, 0.18 mmol),
1-bromo-4-(propane-2-sulfonyl)-benzene (0.048 g, 0.18 mmol),
Cs.sub.2CO.sub.3 (176 mg, 0.54 mmol), Pd.sub.2(dba).sub.3 (4 mg,
0.005 mmol) and X-Phos (4 mg, 0.009 mmol), the title compound (16
mg, 20%) was obtained as a solid.
[1002] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.38 (d,
J=3.03 Hz, 1H) 7.77-7.82 (m, 4H) 7.68-7.69 (m, 1H) 7.66 (s, 1H)
5.04-5.12 (m, 1H) 4.11 (dd, J=11.62, 4.55 Hz, 2H) 3.32-3.39 (m, 2H)
3.13-3.23 (m, 1H) 2.66 (s, 3H) 2.50-2.62 (m, 2H) 1.88 (m, 2H) 1.31
(d, J=6.82 Hz, 6H); MS (ES) m/z 458 (M-1)
Example 116
N-[4-(Ethylsulfonyl)phenyl]-5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4--
yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00195##
[1004] The title compound was prepared in accordance with the
general method E. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (0.05 g, 0.18 mmol),
1-bromo-4-ethanesulfonyl-benzene (0.039 g, 0.18 mmol),
Cs.sub.2CO.sub.3 (176 mg, 0.54 .mu.mol), Pd.sub.2(dba).sub.3 (4 mg,
0.005 mmol) and X-Phos (4 mg, 0.009 mmol), the title compound (21
mg, 26%) was obtained as a solid.
[1005] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.37 (m, 1H)
7.76-7.84 (m, 4H) 7.74 (br. s., 1H) 7.68 (d, J=3.79 Hz, 1H)
5.03-5.13 (m, 1H) 4.10 (dd, J=11.62, 4.55 Hz, 2H) 3.29-3.38 (m, 2H)
3.11 (q, J=7.58 Hz, 2H) 2.66 (s, 3H) 2.60-2.50 (m, 2H) 1.89-1.86
(m, 1H) 1.28 (t, J=7.41 Hz, 3H); MS (ES) m/z 444 (M-1).
Example 117
5-Fluoro-N-{4-[(2-methoxyethyl)sulfonyl]phenyl}-4-[2-methyl-1-(tetrahydro--
2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00196##
[1007] The title compound was prepared in accordance with the
general method E. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (0.05 g, 0.18 mmol),
2-(4-bromophenyl)sulfonyl ethyl ether (obtained from Example
117(a)) (0.05 g, 0.18 mmol), Cs.sub.2CO.sub.3 (176 mg, 0.54 mmol),
Pd.sub.2(dba).sub.3 (4 mg, 0.005 mmol) and X-Phos (4 mg, 0.009
mmol), the title compound (21 mg, 26%) was obtained as a solid.
[1008] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.38 (d,
J=2.78 Hz, 1H) 7.75-7.88 (m, 4H) 7.70 (br. s., 1H) 7.67 (br. s.,
1H) 5.02-5.13 (m, 1H) 4.11 (dd, J=11.62, 4.55 Hz, 2H) 3.75 (t,
J=6.32 Hz, 2H) 3.29-3.42 (m, 4H) 3.27 (s, 3H) 2.66 (s, 3H)
2.50-2.63 (m, 2H) 1.88 (dd, J=12.24, 3.03 Hz, 2H); MS (ES) m/z 474
(M-1)
Example 117(a) 2-[(4-Bromophenyl)sulfonyl]ethyl methyl ether
##STR00197##
[1010] The title compound was prepared in accordance with the
general method I. Using 4-bromobenzenesulfonyl chloride (0.256 g, 1
mmol), Na.sub.2SO.sub.3 (0.126 g, 1 mmol), NaHCO.sub.3 (0. 252 g, 3
mmol.) and 2-bromoethyl methyl ether (0.28 mL, 3 mmol) to give the
title compound (0.132 g, 50%) as an oil.
[1011] .sup.1H NMR (400 MHz, CDCl.sub.3) 5 ppm 7.67-7.83 (m, 4H)
3.73 (t, J=6.06 Hz, 2H) 3.37 (t, J=6.06 Hz, 2H) 3.21 (s, 3H); MS
(ES) m/z 280 (M+1).
Example 118
N-(4-{[2-(Diethylamino)ethyl]sulfonyl}phenyl)-5-fluoro-4-[2-methyl-1-(tetr-
ahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine
##STR00198##
[1013] The title compound was prepared in accordance with the
general method E. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (0.05 g, 0.18 mmol),
[2-(4-bromo-benzenesulfonyl)-ethyl]-diethyl-amine (obtained from
Example 118(a)) (0.058 g, 0.18 mmol), Cs.sub.2CO.sub.3 (176 mg,
0.54 mmol), Pd.sub.2(dba).sub.3 (4 mg, 0.005 mmol) and X-Phos (4
mg, 0.009 mmol), the title compound (50 mg, 54%) was obtained as a
solid.
[1014] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.36 (d,
J=2.78 Hz, 1H) 7.88 (br. s., 1H) 7.74-7.84 (m, 4H) 7.62-7.70 (m,
1H) 5.00-5.15 (m, 1H) 4.08 (dd, J=11.62, 4.55 Hz, 2H) 3.27-3.40 (m,
2H) 3.19-3.27 (m, 2H) 2.85-2.95 (m, 2H) 2.63 (s, 3H) 2.48-2.60 (m,
2H) 2.45 (q, J=7.33 Hz, 4H) 1.81-1.91 (m, 2H) 0.94 (t, J=7.33 Hz,
6H); MS (ES) m/z 515 (M-1).
Example 118(a) 2-[(4-Bromophenyl)sulfonyl]ethyl diethyl-amine
##STR00199##
[1016] The title compound was prepared in accordance with the
general method I. Using 4-bromobenzenesulfonyl chloride (0.256 g, 1
mmol), Na.sub.2SO.sub.3 (0.126 g, 1 mmol), NaHCO.sub.3 (0. 252 g, 3
mmol.) and 2-bromoethyl diethyl amine hydrobromide (0.52 g, 2 mmol)
to give the title compound (0.06 g, 19%) as an oil.
[1017] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.66-7.84 (m,
4H) 3.19-3.29 (m, 2H) 2.86-2.94 (m, 2H) 2.43 (q, J=7.07 Hz, 4H)
0.93 (t, J=7.03 Hz, 6H); MS (ES) m/z 322 (M+2).
Example 119
2-{[4-({5-Fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl-
]pyrimidin-2-yl}amino)phenyl]sulfonyl}ethanol
##STR00200##
[1019] The title compound was prepared in accordance with the
general method E. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (0.05 g, 0.18 mmol),
2-[(4-bromo-phenyl)sulfonyl]ethanol (described in DE3530710) (0.048
g, 0.18 mmol), Cs.sub.2CO.sub.3 (176 mg, 0.54 mmol),
Pd.sub.2(dba).sub.3 (4 mg, 0.005 mmol) and X-Phos (4 mg, 0.009
mmol), the title compound (40 mg, 44%) was obtained as a solid.
[1020] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.37 (d,
J=2.78 Hz, 1H) 7.89 (s, 1H) 7.77-7.86 (m, 4H) 7.66 (d, J=4.04 Hz,
1H) 5.00-5.12 (m, 1H) 4.09 (dd, J=11.62, 4.55 Hz, 2H) 3.96-4.03 (m,
2H) 3.28-3.39 (m, 41H) 2.64 (s, 3H) 2.47-2.60 (m, 2H) 1.81-1.92 (m,
2H);
[1021] MS (ES) m/z 462 (M+1)
Example 120
{5-Fluoro-4-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin-2-yl}-[-
4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine
##STR00201##
[1023] The title compound was prepared in accordance with the
general method E. Using
5-fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne (obtained from Example 120(e)) (0.1 g, 0.38 mmol),
1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.111 g, 0.349
mmol), Cs.sub.2CO.sub.3 (247 mg, 0.76 mmol), Pd.sub.2(dba).sub.3
(17 mg, 0.019 mmol) and X-Phos (18 mg, 0.038 mmol), the title
compound (155 mg, 88%) was obtained as an oil.
[1024] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.38 (m, 1H),
7.88 (m, 2H), 7.71 (m, 4H), 7.38 (s, 1H), 5.35 (m, 1H), 4.06 (m,
2H) 3.34 (m, 2H), 3.05 (m, 4H), 2.27 (s, 3H), 2.12-1.98 (m, 4H); MS
(ES) m/z 502 (M+1).
Example 120(a)
N-(5-Methyl-isoxazol-4-yl)-N-(tetrahydro-pyran-4-yl)-formamide
##STR00202##
[1026] The title compound was prepared following the procedure
described in Example 7(a), with the exception that the product was
purified by flash chromatography (EtOAc). Using
5-methyl-4-amino-isoxazole (Reiter, L. A, J. Org. Chem. 1987, 52,
2714-2726) (2.5 g, 25.48 mmol), tetrahydro-pyran-4-one (0.26 ml,
28.03 mmol) and formic acid (3.2 g, 15.3 mmol) the title compound
was obtained (3.8 g, 71%).
[1027] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.12 (s, 1H),
8.01 (s, 1H), 4.67 (m, 1H), 3.99 (m, 2H), 3.49 (m, 1H), 2.40 (s,
3H), 1.72 (m, 2H), 1.50 (m, 2H).
Example 120(b) 5-Acetyl-1-(tetrahydro-pyran-4-yl)-1H-imidazole
##STR00203##
[1029] The title compound was prepared in accordance with the
general method of Example 7(b), with the exception that the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH, 20:1).
Using
N-(5-Methyl-isoxazol-4-yl)-N-(tetrahydro-pyran-4-yl)-formamide (3.8
g, 18.1 mmol, obtained from Example 120(a)) the title compound was
obtained (2.7 g, 77%).
[1030] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.80 (m, 2H)
5.15 (m, 1H) 4.09 (m, 2H) 3.57 (m, 2H) 2.48 (s, 3H) 2.06 (m, 2H)
1.92 (m, 21H).
Example 120(c)
(E)-3-Dimethylamino-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-propen-
one
##STR00204##
[1032] The title compound was prepared in accordance with the
general method of Example 7(c), with the exception that the product
was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH, 25:1).
Using 5-acetyl-1-(tetrahydro-pyran-4-yl)-1H-imidazole (2.7 g, 13.9
mmol, obtained from Example 120(b)) the title compound was obtained
(3.2 g, 92%).
[1033] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.71-7.61 (m,
3H) 5.53 (m, 1H) 5.37 (m, 1H) 4.07 (m, 2H) 3.57 (m, 2H) 3.10 (br.
s., 3H) 2.93 (br.s., 3H) 2.11 (m, 2H) 1.92 (m, 2H).
Example 120(d)
(Z)-3-Dimethylamino-2-fluoro-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-y-
l]-propenone
##STR00205##
[1035] The title compound was prepared in accordance with the
general method of Example 7(d), with the exception that the product
was purified by flash chromatography (EtOAc/MeOH). Using
(E)-3-dimethylamino-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-propen-
one (3.2 g, 12.85 mmol, obtained from Example 120(d)) the title
compound was obtained (0.68 g, 20%) as an oil.
[1036] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.74 (s, 1H)
7.60 (s, 1H) 6.89 (m, 1H) 5.10 (m, 1H) 4.05 (m, 2H) 3.53 (m, 2H)
3.11 (s, 6H) 2.08 (m, 2H) 1.89 (m, 2H).
Example 120(e)
5-Fluoro-4-[1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-ami-
ne
##STR00206##
[1038] The title compound was prepared in accordance with the
general method B with the exception that guanidine carbonate was
used. Using
(Z)-3-dimethylamino-2-fluoro-1-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-y-
l]-propenone (0.67 g, 2.51 mmol, obtained from Example 120(d)) and
guanidine carbonate (1.13 g, 6.27 mmol) the title compound (0.48 g,
73%) was obtained as a solid after purification by flash
chromatography (CH.sub.2Cl.sub.2/MeOH 20:1).
[1039] .sup.1H NMR (400 MHz, CDCl.sub.3) 5 ppm 8.19 (m, 1H) 7.83
(m, 2H) 5.40 (m, 1H) 4.89 (m, 2H) 4.15 (m, 2H) 3.54 (m, 2H) 2.16
(m, 2H) 2.01 (m, 2H); MS (ES) m/z 264 (M+1).
Example 121
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimidin-4-
-yl}-1-(tetrahydro-pyran-4-yl)-1H-4H-imidazole-2-carbonitrile
##STR00207##
[1041]
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyri-
mid in-4-yl}-1-(tetrahydro-pyran-4-yl)-1H-imidazole-2-carbaldehyde
(obtained from Example 121(a)) (34 mg, 0.064 mmol) was mixed with
NH.sub.2OH.HCl (5 mg, 0.077 mmol) in formic acid (1 mL). The
mixture was heated to reflux and monitored by LC until full
conversion was achieved. Then, the mixtured was extracted and
purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH) to give
the title compound (21 mg, 64%).
[1042] MS (ES) m/z 527 (M+1).
Example 121 (a)
5-{5-Fluoro-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimidin--
4-yl}-1-(tetrahydro-pyran-4-yl)-1H-imidazole-2-carbaldehyde
##STR00208##
[1044]
{5-Fluoro-4-[3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidin--
2-yl}-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine (obtained
from Example 120) (0.315 g, 0.629 mmol) was treated with n-BuLi
(1.8 mL, 1.6M solution in hexane, 2.83 mmol) in THF (10 mL) at low
temperature (-60 to -30.degree. C.) for 30 min. Then, DMF (0.137
mg, 1.89 mmol) was added to the mixture at -70.degree. C. and the
cooling bath was removed. The resulting mixture was quenched with
NH.sub.4Cl (saturated solution) and extracted with
CH.sub.2Cl.sub.2. The title compound (0.1 g, 30%) was obtained
after purification by flash chromatography (CH.sub.2Cl.sub.2/MeOH
20:1).
[1045] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.94 (s, 1H), 8.51
(m, 1H), 7.79-7.68 (m, 6H), 5.33 (m, 1H), 4.07 (m, 2H) 3.38 (m,
2H), 3.03 (m, 4H), 2.71 (m, 2H), 2.48 (m, 4H), 2.26 (s, 3H), 1.80
(m, 4H).
Example 122
{5-Fluoro-4-[2-methyl-3-(tetrahydro-pyran-4-yl)-3H-imidazol-4-yl]-pyrimidi-
n-2-yl}-[4-(tetrahydro-pyran-2-ylmethanesulfonyl)-phenyl]-amine
##STR00209##
[1047] The title compound was prepared in accordance with the
general method E. Using
5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimi-
din-2-amine (obtained from Example 7(e)) (0.05 g, 0.18 mmol),
2-(4-bromo-benzenesulfonylmethyl)-tetrahydro-pyran (obtained from
Example 122(a)) (0.057 g, 0.18 mmol), Cs.sub.2CO.sub.3 (176 mg,
0.54 mmol), Pd.sub.2(dba).sub.3 (4 mg, 0.005 mmol) and X-Phos (4
mg, 0.009 mmol), the title compound (21 mg, 23%) was obtained as a
solid.
[1048] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.37 (d,
J=3.03 Hz, 1H) 7.80-7.88 (m, 2H) 7.71-7.78 (m, 2H) 7.63-7.71 (m,
2H) 4.92-5.19 (m, 1H) 4.10 (dd, J=11.75, 4.42 Hz, 2H) 3.76-3.92 (m,
2H) 3.28-3.41 (m, 5H) 3.12 (dd, J=14.40, 3.79 Hz, 1H) 2.66 (s, 3H)
2.47-2.61 (m, 2H) 1.23-1.93 (3m, 7H); MS (ES) m/z 516 (M+1).
Example 122(a)
2-(4-Bromo-benzenesulfonylmethyl)-tetrahydro-pyran
##STR00210##
[1050] The title compound was prepared in accordance with the
general method I. Using 4-bromobenzenesulfonyl chloride (0.256 g, 1
mmol), Na.sub.2SO.sub.3 (0.126 g, 1 mmol), NaHCO.sub.3 (0. 252 g, 3
mmol.) and 2-bromomethyl-tetrahydro-pyran (0.128 mL, 1 mmol) to
give the title compound (0.06 g, 19%) as an oil.
[1051] MS (ES) m/z 321 (M+1).
Pharmaceutical Compositions
[1052] According to one aspect of the present invention there is
provided a pharmaceutical composition comprising a compound of
formula I, as a free base or a pharmaceutically acceptable salt,
solvate or solvate of salt thereof, for use in the prevention
and/or treatment of conditions associated with glycogen synthase
kinase-3.
[1053] The composition may be in a form suitable for oral
administration, for example as a tablet, for parenteral injection
as a sterile solution or suspension. In general the above
compositions may be prepared in a conventional manner using
pharmaceutically carriers or diluents. Suitable daily doses of the
compounds of formula I in the treatment of a mammal, including man,
are approximately 0.01 to 250 mg/kg bodyweight at peroral
administration and about 0.001 to 250 mg/kg bodyweight at
parenteral administration. The typical daily dose of the active
ingredients varies within a wide range and will depend on various
factors such as the relevant indication, the route of
administration, the age, weight and sex of the patient and may be
determined by a physician.
[1054] A compound of formula I, or a pharmaceutically acceptable
salt, solvate or solvate of salt thereof, can be used on its own
but will usually be administered in the form of a pharmaceutical
composition in which the formula I compound/salt/solvate (active
ingredient) is in association with a pharmaceutically acceptable
excipient, diluent or carrier. Dependent on the mode of
administration, the pharmaceutical composition may comprise from
0.05 to 99% w (percent by weight), for example from 0.10 to 50% w,
of active ingredient, all percentages by weight being based on
total composition.
[1055] An excipient, diluent or carrier includes water, aqueous
polyethylene glycol, magnesium carbonate, magnesium stearate, talc,
a sugar (such as lactose), pectin, dextrin, starch, tragacanth,
microcrystalline cellulose, methyl cellulose, sodium carboxymethyl
cellulose or cocoa butter.
[1056] A composition of the invention can be in tablet or
injectable form. The tablet may additionally comprise a
disintegrant and/or may be coated (for example with an enteric
coating or coated with a coating agent such as hydroxypropyl
methylcellulose).
[1057] The invention further provides a process for the preparation
of a pharmaceutical composition of the invention which comprises
mixing a compound of formula I, or a pharmaceutically acceptable
salt, solvate or solvate of salt thereof, as hereinbefore defined,
with a pharmaceutically acceptable excipient, diluent or
carrier.
[1058] An example of a pharmaceutical composition of the invention
is an injectable solution containing a compound of the invention,
or a a pharmaceutically acceptable salt, solvate or solvate of salt
thereof, as hereinbefore defined, and sterile water, and, if
necessary, either sodium hydroxide or hydrochloric acid to bring
the pH of the final composition to about pH 5, and optionally a
surfactant to aid dissolution.
Medical Use
[1059] Surprisingly, it has been found that the compounds defined
in the present invention, as a free base or a pharmaceutically
acceptable salt thereof, are well suited for inhibiting glycogen
synthase kinase-3 (GSK3). Accordingly, the compounds of the present
invention are expected to be useful in the prevention and/or
treatment of conditions associated with glycogen synthase kinase-3
activity, i.e. the compounds may be used to produce an inhibitory
effect of GSK3 in mammals, including man, in need of such
prevention and/or treatment.
[1060] GSK3 is highly expressed in the central and peripheral
nervous system and in other tissues. Thus, it is expected that
compounds of the invention are well suited for the prevention
and/or treatment of conditions associated with glycogen synthase
kinase-3 in the central and peripheral nervous system. In
particular, the compounds of the invention are expected to be
suitable for prevention and/or treatment of conditions associated
with especially, dementia, Alzheimer's Disease, Parkinson's
Disease, Frontotemporal dementia Parkinson's Type, Parkinson
dementia complex of Guam, HIV dementia, diseases with associated
neurofibrillar tangle pathologies and dementia pugilistica.
[1061] Other conditions are selected from the group consisting of
amyotrophic lateral sclerosis, corticobasal degeneration, Down
syndrome, Huntington's Disease, postencephelatic parkinsonism,
progressive supranuclear palsy, Pick's Disease, Niemann-Pick's
Disease, stroke, head trauma and other chronic neurodegenerative
diseases, Bipolar Disease, affective disorders, depression,
schizophrenia, cognitive disorders, hair loss and contraceptive
medication.
[1062] Further conditions are selected from the group consisting of
predemented states, Mild Cognitive Impairment, Age-Associated
Memory Impairment, Age-Related Cognitive Decline, Cognitive
Impairment No Dementia, mild cognitive decline, mild neurocognitive
decline, Late-Life Forgetfulness, memory impairment and cognitive
impairment, vascular dementia, dementia with Lewy bodies,
Frontotemporal dementia and androgenetic alopecia and Type I and
Type II diabetes, diabetic neuropathy and diabetes related
disorders.
[1063] One embodiment of the invention relates to the prevention
and/or treatment of dementia and Alzheimer's Disease.
[1064] Another embodiment of the invention relates to the
prevention and/or treatment of bone-related disorders.
[1065] The dose required for the therapeutic or preventive
treatment of a particular disease will necessarily be varied
depending on the host treated, the route of administration and the
severity of the illness being treated.
[1066] The present invention relates also to the use of a compound
of formula I as defined hereinbefore, in the manufacture of a
medicament for the prevention and/or treatment of conditions
associated with glycogen synthase kinase-3.
[1067] In the context of the present specification, the term
"therapy" also includes "prevention" unless there are specific
indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly.
[1068] The invention also provides for a method of treatment and/or
prevention of conditions associated with glycogen synthase kinase-3
comprising administering to a mammal, is including man in need of
such treatment and/or prevention a therapeutically effective amount
of a compound of formula I, as hereinbefore defined.
Non-Medical Use
[1069] In addition to their use in therapeutic medicine, the
compounds of formula I as a free base or a pharmaceutically
acceptable salt thereof, are also useful as pharmacological tools
in the development and standardisation of in vitro and in vivo test
systems for the evaluation of the effects of inhibitors of GSK3
related activity in laboratory animals such as cats, dogs, rabbits,
monkeys, rats and mice, as part of the search for new therapeutics
agents.
Pharmacology
[1070] Determination of ATP competition in Scintillation Proximity
GSK3.beta. Assay.
GSK3.beta. Scintillation Proximity Assay.
[1071] The competition experiments were carried out in duplicate
with 10 different concentrations of the inhibitors in clear-bottom
microtiter plates (Wallac, Finland). A biotinylated peptide
substrate,
Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO.sub.3H.sub.2)-Pro-G-
ln-Leu (AstraZeneca, Lund), was added at a final concentration of 1
.mu.M in an assay buffer containing 1 mU recombinant human
GSK3.beta. (Dundee University, UK), 12 mM morpholinepropanesulfonic
acid (MOPS), pH 7.0, 0.3 mM EDTA, 0.01% .beta.-mercaptorethanol,
0.004% Brij 35 (a natural detergent), 0.5% glycerol and 0.5 .mu.g
BSA/25 .mu.l. The reaction was initiated by the addition of 0.04
.mu.Ci [.gamma.-.sup.33P]ATP (Amersham, UK) and unlabelled ATP at a
final concentration of 1 .mu.M and assay volume of 25 .mu.l. After
incubation for 20 minutes at room temperature, each reaction was
terminated by the addition of 25 .mu.l stop solution containing 5
mM EDTA, 50 .mu.M ATP, 0.1% Triton X-100 and 0.25 mg streptavidin
coated Scintillation Proximity Assay (SPA) beads (Amersham, UK).
After 6 hours the radioactivity was determined in a liquid
scintillation counter (1450 MicroBeta Trilux, Wallac). The
inhibition curves were analysed by non-linear regression using
GraphPad Prism, USA. The K.sub.m value of ATP for GSK30, used to
calculate the inhibition constants (K.sub.i) of the various
compounds, was 20 .mu.M.
[1072] The following abbreviations have been used:
MOPS Morpholinepropanesulfonic acid EDTA Ethylenediaminetetraacetic
acid
BSA Bovin Serum Albumin
ATP Adenosine Triphosphate
SPA Scintillation Proximity Assay
[1073] GSK3 Glycogen synthase kinase 3
Results
[1074] Typical K.sub.i values for the compounds of the present
invention are in the range of about 0.001 to about 10,000 nM. Other
values for K.sub.i are in the range of about 0.001 to about 1000
nM. Further values for K.sub.i are in the range of about 0.001 nM
to about 300 nM.
TABLE-US-00002 TABLE 1 Specimen results from assay. Example no
K.sub.i (nM) n 1 10 3 17 14 4 22 22 3 29 126 2
* * * * *
References